U.S. patent application number 11/955204 was filed with the patent office on 2008-08-14 for hydroxy-substituted aryl sulfamide derivatives and methods of their use.
This patent application is currently assigned to Wyeth. Invention is credited to Andrew Fensome, Joel Adam Goldberg, Charles William Mann, Casey Cameron McComas, David John O'Neill, Joseph Peter Sabatucci, Eugene Anthony Terefenko, Eugene John Trybulski, An Thien Vu, Puwen Zhang.
Application Number | 20080194654 11/955204 |
Document ID | / |
Family ID | 39273293 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080194654 |
Kind Code |
A1 |
McComas; Casey Cameron ; et
al. |
August 14, 2008 |
HYDROXY-SUBSTITUTED ARYL SULFAMIDE DERIVATIVES AND METHODS OF THEIR
USE
Abstract
The present invention is directed to hydroxy-substituted aryl
sulfamide derivatives of formula I: ##STR00001## or a
pharmaceutically acceptable salt, stereoisomer or tautomer thereof,
which are monoamine reuptake inhibitors, compositions containing
these derivatives, and methods of their use for the prevention and
treatment of conditions, including, inter alia, vasomotor symptoms,
sexual dysfunction, gastrointestinal disorders and genitourinary
disorder, depression disorders, endogenous behavioral disorders,
cognitive disorders, diabetic neuropathy, pain, and other diseases
or disorders.
Inventors: |
McComas; Casey Cameron;
(Phoenixville, PA) ; Fensome; Andrew; (Wayne,
PA) ; Goldberg; Joel Adam; (Philadelphia, PA)
; Mann; Charles William; (Plymouth Meeting, PA) ;
O'Neill; David John; (Collegeville, PA) ; Sabatucci;
Joseph Peter; (Collegeville, PA) ; Terefenko; Eugene
Anthony; (Center Valley, PA) ; Trybulski; Eugene
John; (Huntingdon Valley, PA) ; Vu; An Thien;
(Pottstown, PA) ; Zhang; Puwen; (Audubon,
PA) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
39273293 |
Appl. No.: |
11/955204 |
Filed: |
December 12, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60869644 |
Dec 12, 2006 |
|
|
|
Current U.S.
Class: |
514/361 ;
548/126 |
Current CPC
Class: |
A61P 3/00 20180101; C07D
285/14 20130101; A61P 25/02 20180101; A61P 25/04 20180101; A61P
15/00 20180101; A61P 25/22 20180101; A61P 25/00 20180101; A61P 7/00
20180101; A61P 13/00 20180101; A61P 1/00 20180101; A61P 21/00
20180101; C07D 417/06 20130101; A61P 25/28 20180101; A61P 29/00
20180101; A61P 9/00 20180101; C07D 417/04 20130101; A61P 25/24
20180101; A61P 25/20 20180101; A61P 7/12 20180101 |
Class at
Publication: |
514/361 ;
548/126 |
International
Class: |
A61K 31/433 20060101
A61K031/433; C07D 285/14 20060101 C07D285/14; A61P 15/00 20060101
A61P015/00; A61P 1/00 20060101 A61P001/00; A61P 21/00 20060101
A61P021/00; A61P 25/24 20060101 A61P025/24; A61P 7/12 20060101
A61P007/12; A61P 29/00 20060101 A61P029/00 |
Claims
1. A compound of formula I: ##STR00102## or a tautomer or
pharmaceutically acceptable salt thereof; wherein: n is an integer
from 0 to 4; m is an integer from 1 to 6; X is --CH.sub.2--;
R.sup.1 is, independently at each occurrence, H, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein
each aryl or heteroaryl is independently substituted with 0-3
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, or alkynyl groups; and each
arylsulfonamide or arylamido is independently substituted with 0-3
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido groups; R.sup.2 is aryl or
heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, arylamido, or aryl or heteroaryl optionally substituted
with alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; R.sup.3 and
R.sup.4 are, independently, H, alkyl, arylalkyl or
heteroarylmethyl, wherein each of alkyl, arylalkyl or
heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups, provided that neither R.sup.3 or
R.sup.4 contain an aminoalkyl group; represents an S-isomer,
R-isomer or racemate; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
2. The compound of claim 1, wherein each R.sup.1 is H.
3. The compound of claim 1, wherein R.sup.2 is: ##STR00103##
wherein, each R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
independently selected from the group consisting of H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, or arylamido.
4. The compound of claim 3, wherein R.sup.9 is F.
5. The compound of claim 4, wherein R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are H.
6. The compound of claim 3, wherein R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 are H, halo, alkyl or alkoxy.
7. The compound of claim 1, wherein R.sup.3 is methyl.
8. The compound of claim 1, wherein R.sup.4 is H.
9. The compound of claim 1, wherein m is an integer from 2 to
6.
10. The compound of claim 1, wherein m is 2.
11. The compound of claim 1, wherein ring A comprises all carbon
atoms.
12. The compound of claim 1, wherein R.sup.2 is pyridinyl,
methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or
quinolinyl.
13. The compound of claim 1, wherein R.sup.2 is phenyl,
fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl,
fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl
trifluoromethoxy-phenyl, methyl-fluoro-phenyl,
methoxy-fluoro-phenyl, or naphthyl.
14. The compound of claim 1, wherein represents an S-isomer.
15. The compound of claim 1, wherein represents an R-isomer.
16. The compound of claim 3, wherein: R.sup.1 is H; R.sup.9 is F;
R.sup.5, R.sup.6, R.sup.7 and R.sup.3 are H; R.sup.3 is methyl;
R.sup.4 is H; m is 2; and represents an S-isomer.
17. The compound of claim 1, selected from the group consisting of:
##STR00104## ##STR00105## ##STR00106## ##STR00107##
18. The compound of claim 1, selected from the group consisting of:
1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
butan-2-ol;
(2R)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol;
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol;
3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl}phenol:
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol;
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)pentan-2-ol;
(2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]butan-2-ol;
(2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)pentan-2-ol;
(2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)pentan-2-ol;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)but-
an-2-ol;
1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1-
(3H)-yl)butan-2-ol;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino-
)butan-2-ol;
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)--
yl)butan-2-ol;
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-ol;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)bu-
tan-2-ol;
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(-
methylamino)butan-2-ol;
(2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H-
)-yl)butan-2-ol;
(2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H-
)-yl)butan-2-ol;
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropyl-
amino)butan-2-ol;
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropyl-
amino)butan-2-ol;
(2S)-1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1-
(3H)-yl)butan-2-ol;
(2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(-
3H)-yl)butan-2-ol;
(2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(-
3H)-yl)butan-2-ol;
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamin-
o)butan-2-ol;
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamin-
o)butan-2-ol;
(2S)-1-(cyclopropylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclopropylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclopropylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzot-
hiadiazol-1(3H)-yl]butan-2-ol;
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylami-
no)butan-2-ol;
(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2S)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol;
(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]butan-2-ol;
(2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol;
(2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol;
(2R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol;
(2R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol;
(2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]butan-2-ol;
(2R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol;
(2R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol;
(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol;
(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol;
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(isopropylamino)butan-2-ol;
(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiaz-
ol-1(3H)-yl]butan-2-ol; and pharmaceutically acceptable salts
thereof.
19. The compound of claim 1, wherein said pharmaceutically
acceptable salt is a hydrochloride or dihydrochloride.
20. A composition, comprising: a. at least one compound of formula
I: ##STR00108## or a tautomer or pharmaceutically acceptable salt
thereof; wherein: n is an integer from 0 to 4; m is an integer from
1 to 6; X is --CH.sub.2--; R.sup.1 is, independently at each
occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide
alkylamido, or arylamido; wherein each aryl or heteroaryl is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl groups; and each arylsulfonamide or arylamido is
independently substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido
groups; R.sup.2 is aryl or heteroaryl substituted with 0-4 alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl
or heteroaryl optionally substituted with alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
or alkynyl; R.sup.3 and R.sup.4 are, independently, H, alkyl,
arylalkyl or heteroarylmethyl, wherein each of alkyl, arylalkyl or
heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups, provided that neither R.sup.3 or
R.sup.4 contain an aminoalkyl group; represents an S-isomer,
R-isomer or racemate; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N; and b. at least one pharmaceutically
acceptable carrier.
21. A method for treating or preventing a condition selected from
the group consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, endogenous
behavioral disorder, cognitive disorder, diabetic neuropathy, pain,
and combinations thereof in a subject in need thereof, comprising
the step of: administering to said subject an effective amount of a
compound of formula I: ##STR00109## or a tautomer or
pharmaceutically acceptable salt thereof; wherein: n is an integer
from 0 to 4; m is an integer from 1 to 6; X is --CH.sub.2--;
R.sup.1 is, independently at each occurrence, H, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein
each aryl or heteroaryl is independently substituted with 0-3
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, or alkynyl groups; and each
arylsulfonamide or arylamido is independently substituted with 0-3
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, or alkylamido groups; R.sup.2 is aryl or
heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, arylamido, or aryl or heteroaryl optionally substituted
with alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; R.sup.3 and
R.sup.4 are, independently, H, alkyl, arylalkyl or
heteroarylmethyl, wherein each of alkyl, arylalkyl or
heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups, provided that neither R.sup.3 or
R.sup.4 contain an aminoalkyl group; represents an S-isomer,
R-isomer or racemate; and wherein 1-3 carbon atoms in ring A may
optionally be replaced with N.
22. The method of claim 21, wherein said vasomotor symptom is hot
flush.
23. The method of claim 21, wherein said sexual dysfunction is
desire-related or arousal-related.
24. The method of claim 21, wherein said gastrointestinal disorder
or said genitourinary disorder is stress incontinence or urge
incontinence.
25. The method of claim 21, wherein said condition is chronic
fatigue syndrome or fibromyalgia syndrome.
26. The method of claim 20, wherein said condition is a depression
disorder selected from the group consisting of major depressive
disorder, generalized anxiety disorder, panic disorder, attention
deficit disorder with or without hyperactivity, sleep disturbance,
social phobia, and combinations thereof.
27. The method of claim 21, wherein said condition is diabetic
neuropathy.
28. The method of claim 21, wherein said condition is pain.
29. The method of claim 28, wherein said pain is acute centralized
pain, acute peripheral pain, or a combination thereof.
30. The method of claim 28, wherein said pain is chronic
centralized pain, chronic peripheral pain, or a combination
thereof.
31. The method of claim 28, wherein said pain is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain,
inflammatory pain, or a combination thereof.
32. The method of claim 31, wherein said neuropathic pain is
associated with diabetes, post traumatic pain of amputation, lower
back pain, cancer, chemical injury, toxins, major surgery,
peripheral nerve damage due to traumatic injury compression,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, burns, central pain
conditions related to thalamic conditions, or a combination
thereof.
33. The method of claim 32, wherein said neuropathic pain is
post-herpetic neuralgia.
34. The method of claim 31, wherein said visceral pain is
associated with ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, or a combination thereof.
35. The method of claim 28, wherein said subject is female; and the
pain is female-specific pain.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) to co-pending U.S. Provisional Application Ser. No.
60/869,644, filed Dec. 12, 2006, which is hereby incorporated by
reference in its entirety.
FIELD
[0002] The present invention relates to hydroxy-substituted aryl
sulfamide derivatives, which are monoamine reuptake inhibitors,
compositions containing these derivatives, and methods of their use
for the prevention and treatment of diseases or disorders including
vasomotor symptoms, depression disorders, endogenous behavioral
disorders, cognitive disorders, sexual dysfunction, or pain
conditions, in particular vasomotor symptoms.
BACKGROUND
[0003] Vasomotor symptoms (VMS), referred to as hot flushes and
night sweats, are the most common symptoms associated with
menopause, occurring in 60% to 80% of all women following natural
or surgically-induced menopause. VMS are likely an adaptive
response of the central nervous system (CNS) to declining sex
steroids. To date, the most effective therapies for VMS are
hormone-based treatments, including estrogens and/or some
progestins. Hormonal treatments are very effective at alleviating
VMS, but they are not appropriate for all women.
[0004] VMS are caused by fluctuations of sex steroid levels and can
be disruptive and disabling in both males and females. A hot flush
can last up to thirty minutes and vary in their frequency from
several times a week to multiple occurrences per day. The patient
experiences a hot flush as a sudden feeling of heat that spreads
quickly from the face to the chest and back and then over the rest
of the body. It is usually accompanied by outbreaks of profuse
sweating, and may sometimes occur several times an hour, and it
often occurs at night. Hot flushes and outbreaks of sweats
occurring during the night can cause sleep deprivation.
Psychological and emotional symptoms are also observed, such as
nervousness, fatigue, irritability, insomnia, depression, memory
loss, headache, anxiety, nervousness or inability to concentrate,
and are caused by the sleep deprivation following hot flush and
night sweats (Kramer et al., In: Murphy et al., 3.sup.rd Int'l
Symposium on Recent Advances in Urological Cancer Diagnosis and
Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).
[0005] Hot flushes may be even more severe in women treated for
breast cancer for several reasons. Many survivors of breast cancer
are given tamoxifen, the most prevalent side effect of which is hot
flush, and many women treated for breast cancer undergo premature
menopause from chemotherapy Women with a history of breast cancer
are also generally been denied estrogen therapy because of concerns
about potential recurrence of breast cancer (Loprinzi, et al.,
Lancet, 2000, 356(9247): 2059-2063).
[0006] Men also experience hot flushes following steroid hormone
(androgen) withdrawal. This is true in cases of age-associated
androgen decline (Katovich, et al., Proceedings of the Society for
Experimental Biology & Medicine, 1990, 193(2): 129-35) as well
as in extreme cases of hormone deprivation associated with
treatments for prostate cancer (Berendsen, et al., European Journal
of Pharmacology, 2001, 419(1): 47-54. As many as one-third of these
patients will experience persistent and frequent symptoms severe
enough to cause significant discomfort and inconvenience.
[0007] The precise mechanism of these vasomotor symptoms is unknown
but generally is thought to represent disturbances to normal
homeostatic mechanisms controlling thermoregulation and vasomotor
activity (Kronenberg et al., "Thermoregulatory Physiology of
Menopausal Hot Flashes: A Review," Can. J. Physiol. Pharmacol.,
1987, 65:1312-1324).
[0008] The fact that estrogen treatment (e.g. estrogen replacement
therapy) relieves the symptoms establishes the link between these
symptoms and an estrogen deficiency. For example, the menopausal
stage of life is associated with a wide range of other acute
symptoms as described above and these symptoms are generally
estrogen responsive.
[0009] It has been suggested that estrogens may stimulate the
activity of both the norepinephrine (NE) and/or serotonin (5-HT)
systems (J. Pharmacology & Experimental Therapeutics, 1986,
236(3) 646-652). It is hypothesized that estrogens modulate NE and
5-HT levels providing homeostasis in the thermoregulatory center of
the hypothalamus. The descending pathways from the hypothalamus via
brainstem/spinal cord and the adrenals to the skin are involved in
maintaining normal skin temperature. The action of NE and 5-HT
reuptake inhibitors is known to impinge on both the CNS and
peripheral nervous system (PNS). The pathophysiology of VMS is
mediated by both central and peripheral mechanisms and, therefore,
the interplay between the CNS and PNS may account for the efficacy
of dual acting SRI/NRIs in the treatment of thermoregulatory
dysfunction. In fact, the physiological aspects and the CNS/PNS
involvement in VMS may account for the lower doses proposed to
treat VMS (Loprinzi, et al., Lancet, 2000, 356:2059-2063; Stearns
et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat
the behavioral aspects of depression. The interplay of the CNS/PNS
in the pathophysiology of VMS supports the claims that the
norepinephrine system could be targeted to treat VMS.
[0010] Although VMS are most commonly treated by hormone therapy,
some patients cannot tolerate estrogen treatment (Berendsen,
Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996,
383(6598): 306). In addition, hormone replacement therapy is
usually not recommended for women or men with or at risk for
hormonally sensitive cancers (e.g. breast or prostate cancer).
Thus, non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs]
and clonidine) are being evaluated clinically. WO9944601 discloses
a method for decreasing hot flushes in a human female by
administering fluoxetine. Other options have been studied for the
treatment of hot flushes, including steroids, alpha-adrenergic
agonists, and beta-blockers, with varying degree of success
(Waldinger et al., Maturitas, 2000, 36(3): 165-168).
[0011] .alpha..sub.2--Adrenergic receptors play a role in
thermoregulatory dysfunctions (Freedman et al., Fertility &
Sterility, 2000, 74(1): 20-3). These receptors are located both
pre- and post-synaptically and mediate an inhibitory role in the
central and peripheral nervous system. There are four distinct
subtypes of the adrenergic.sub..alpha.2 receptors, i.e., are
.alpha..sub.2A, .alpha..sub.2B, .alpha..sub.2C and .alpha..sub.2D
(Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther.,
1995, 68: 175). A non-select .alpha..sub.2-adrenoceptor antagonist,
yohimbine, induces a flush and an .alpha..sub.2-adrenergic receptor
agonist, clonidine, alleviates the yohimbine effect (Katovich, et
al., Proceedings of the Society for Experimental Biology &
Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility &
Sterility, 2000, 74(1): 20-3). Clonidine has been used to treat hot
flush. However, using such treatment is associated with a number of
undesired side effects caused by high doses necessary to abate hot
flush described herein and known in the related arts.
[0012] Chronic pain comes in many forms, including visceral,
inflammatory or neuropathic and crosses all therapeutic areas. It
is a debilitating condition that exerts a high social cost in terms
of productivity, economic impact and quality of life and current
therapies have limited efficacy. Currently, first-line
pharmacological treatments for neuropathic pain (i.e., diabetic
neuropathy and post-herpetic neuralgia) and fibromyalgia include
off-label use of the tricyclic (TCA) antidepressants (e.g.,
amytriptyline) and anticonvulsants (e.g., gabapentin) (Collins et
al., J. Pain Symptom Manage. 2000, 20(6):449-58; and Marcus Expert
Opin Pharmacother. 2003, 4(10): 1687-95.). However, these therapies
are only effective in 30-50% of patients and produce only a partial
reduction in pain (.about.50%). In addition, the clinical benefits
of these therapies are often outweighed by the side effects,
including dry mouth and sedation. Therefore, newer classes of
compounds including non-TCA antidepressants are being evaluated
preclinically and clinically for chronic pain indications, and
recently duloxetine was approved for the treatment of diabetic
neuropathy. Although more tolerable than the older tricyclic
antidepressants, these newer compounds are not devoid of side
effects that include sexual dysfunction, weight gain and
nausea.
[0013] While the precise pathophysiological mechanisms involved in
the development and maintenance of chronic pain states are not
fully understood, the pathways involved in pain perception and
modulation have been well described and characterized (Gebhart, In:
Yaksh T L, editor. Spinal afferent processing, New York: Plenum,
1986. pp 391-416; Fields, et al., Annual Review of Neuroscience
1991, 14: 219-245; Fields, et al. In: Wall P D, Melzack R, editors.
Textbook of pain, London: Churchill Livingstone, 1999, pp 309-329;
Millan, et al. Progress in Neurobiology; 2002, 66:355-474). A major
component of this descending pain inhibitory system involves the
noradrenergic pathway (Zhuo, et al., Brain Research 1991;
550:35-48; Holden, et al. Neuroscience 1999; 91: 979-990). It is
assumed that norepinephrine (NE), and to a lesser extent serotonin
(5-HT) reuptake inhibitor NRIs and SRIs, attenuate pain by
preventing presynaptic reuptake of NE/5-HT leading to increased
postsynaptic NE/5-HT levels and sustained activation of this
descending pain inhibitory pathway. A meta-analysis of
antidepressants and neuropathic pain comparing the efficacy of
known NRIs, mixed NRI/SRIs and SRIs determined that compounds with
NRI activity were more effective in reducing pain, and that select
SRIs did not significantly differ from placebo (Collins et al., J.
Pain Symptom Manage. 2000, 20(6): 449-58). This analysis suggests
that compounds with greater NRI versus SRI activity will be more
effective for the treatment of pain.
[0014] Given the complex multifaceted nature of pain and of
thermoregulation and the interplay between the CNS and PNS in
maintaining thermoregulatory the homeostasis, multiple therapies
and approaches can be developed to target the treatment of pain and
vasomotor symptoms. The present invention provides novel compounds
and compositions containing these compounds directed to these and
other important uses.
SUMMARY
[0015] The present invention is directed to aryl sulfamide
derivatives, which are monoamine reuptake inhibitors, compositions
containing these derivatives, and methods of their use for the
prevention and treatment of conditions, including, inter alia,
vasomotor symptoms (such as hot flush), sexual dysfunction (such as
desire-related or arousal-related dysfunction), gastrointestinal
disorders and genitourinary disorder (such as stress incontinence
or urge incontinence), chronic fatigue syndrome, fibromyalgia
syndrome, depression disorders (such as major depressive disorder,
generalized anxiety disorder, panic disorder, attention deficit
disorder with or without hyperactivity, sleep disturbance, and
social phobia), diabetic neuropathy, pain, and combinations
thereof.
[0016] One aspect of the invention provides a compound of formula
I:
##STR00002## [0017] or a tautomer or pharmaceutically acceptable
salt thereof; [0018] wherein: [0019] n is an integer from 0 to 4;
[0020] m is an integer from 1 to 6; [0021] X is --CH.sub.2--;
[0022] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or
arylamido; wherein each aryl or heteroaryl is independently
substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups;
and each arylsulfonamide or arylamido is independently substituted
with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido groups; [0023]
R.sup.2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl
optionally substituted with alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; [0024] R.sup.3 and R.sup.4 are, independently, H, alkyl,
arylalkyl or heteroarylmethyl, wherein each of alkyl, arylalkyl or
heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups, provided that neither R.sup.3 or
R.sup.4 contain an aminoalkyl group; [0025] represents an S-isomer,
R-isomer or racemate; and [0026] wherein 1-3 carbon atoms in ring A
may optionally be replaced with N.
[0027] Another aspect of the invention provides a composition,
comprising:
[0028] a. at least one compound of formula I; and
[0029] b. at least one pharmaceutically acceptable carrier.
[0030] Another aspect of the invention provides a method for
treating or preventing a condition selected from the group
consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, endogenous
behavioral disorder, cognitive disorder, diabetic neuropathy, pain,
and combinations thereof in a subject in need thereof, comprising
the step of:
[0031] administering to said subject an effective amount of a
compound of formula I.
[0032] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
[0033] the process comprising:
[0034] reacting HN(R.sup.3)(R.sup.4) a compound of formula IA:
##STR00003##
[0035] wherein the compound of formula I is formed.
[0036] In another aspect of the invention, the compound of formula
IA is formed by:
[0037] activating a primary or secondary hydroxy group on the
compound of formula IB:
##STR00004## [0038] to form an activated compound of formula IB;
and [0039] contacting the activated compound of formula IB with a
base, wherein the compound of formula IA is formed.
[0040] In another aspect of the invention, the compound of formula
IB is formed by:
[0041] deprotecting a compound of formula IC:
##STR00005##
[0042] In another aspect of the invention, the compound of formula
IC is prepared by:
[0043] oxidizing a compound of formula ID:
##STR00006##
[0044] In another aspect of the invention, the compound of formula
ID is prepared by:
[0045] reacting thionyl chloride (SOCl.sub.2) with a compound of
formula IE:
##STR00007##
[0046] In another aspect of the invention, the compound of formula
IE is prepared by:
[0047] reacting a compound of formula IF:
##STR00008##
[0048] with a compound of formula IG:
##STR00009##
[0049] wherein, the compound of formula IE is formed.
[0050] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating embodiments
of the invention, are given by way of illustration only, since
various changes and modifications within the spirit and scope of
the invention will become apparent to those skilled in the art from
this detailed description.
DETAILED DESCRIPTION
[0051] The following definitions are provided for the full
understanding of terms and abbreviations used in this
specification.
[0052] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include the plural reference unless the
context clearly indicates otherwise. Thus, for example, a reference
to "an antagonist" includes a plurality of such antagonists, and a
reference to "a compound" is a reference to one or more compounds
and equivalents thereof known to those skilled in the art, and so
forth.
[0053] The abbreviations in the specification correspond to units
of measure, techniques, properties, or compounds as follows: "min"
means minutes, "h" means hour(s), ".mu.L" means microliter(s), "mL"
means milliliter(s), "mM" means millimolar, "M" means molar,
"mmole" means millimole(s), "cm" means centimeters, "SEM" means
standard error of the mean and "IU" means International Units.
".DELTA..degree. C." and .DELTA. "ED.sub.50 value" means dose which
results in 50% alleviation of the observed condition or effect (50%
mean maximum endpoint).
[0054] "Norepinephrine transporter" is abbreviated NET.
[0055] "Human norepinephrine transporter" is abbreviated hNET.
[0056] "Serotonin transporter" is abbreviated SERT.
[0057] "Human serotonin transporter" is abbreviated hSERT.
[0058] "Norepinephrine reuptake inhibitor" is abbreviated NRI.
[0059] "Selective norepinephrine reuptake inhibitor" is abbreviated
SNRI.
[0060] "Serotonin reuptake inhibitor" is abbreviated SRI.
[0061] "Selective serotonin reuptake inhibitor" is abbreviated
SSRI.
[0062] "Norepinephrine" is abbreviated NE.
[0063] "Serotonin is abbreviated 5-HT.
[0064] "Subcutaneous" is abbreviated sc.
[0065] "Intraperitoneal" is abbreviated ip.
[0066] "Oral" is abbreviated po.
[0067] In the context of this disclosure, a number of terms are
utilized. The term "treat," "treatment" or "treating" as used
herein includes preventative (e.g., prophylactic), curative or
palliative treatment.
[0068] The term "effective amount," as used herein, refers to an
amount effective, at dosages, and for periods of time necessary, to
achieve the desired result with respect to treatment of a given
disease or disorder. An effective amount is also one in which any
toxic or detrimental effects of the components are outweighed by
the therapeutically beneficial effects. In particular, with respect
to vasomotor symptoms, "effective amount" refers to the amount of
compound or composition of compounds that would increase
norepinephrine levels to compensate in part or total for the lack
of steroid availability in subjects subject afflicted with a
vasomotor symptom. Varying hormone levels will influence the amount
of compound required in the present invention. For example, the
pre-menopausal state may require a lower level of compound due to
higher hormone levels than the peri-menopausal state.
[0069] The effective amount of components of the present invention
will vary from patient to patient not only with the particular
compound, component or composition selected, the route of
administration, and the ability of the components (alone or in
combination with one or more additional active agents) to elicit a
desired response in the individual, but also with factors such as
the disease state or severity of the condition to be alleviated,
hormone levels, age, sex, weight of the individual, the state of
being of the patient, and the severity of the pathological
condition being treated, concurrent medication or special diets
then being followed by the particular patient, and other factors
which those skilled in the art will recognize, with the appropriate
dosage ultimately being at the discretion of the attendant
physician. Dosage regimens may be adjusted to provide the improved
therapeutic response.
[0070] Preferably, the compounds of the present invention are
administered at a dosage and for a time such that the number of hot
flushes is reduced as compared to the number of hot flushes prior
to the start of treatment. Such treatment can also be beneficial to
reduce the overall severity or intensity distribution of any hot
flushes still experienced, as compared to the severity of hot
flushes prior to the start of the treatment. With respect to sexual
dysfunction, gastrointestinal disorder, genitourinary disorder,
chronic fatigue syndrome, fibromyalgia syndrome, depression
disorder, diabetic neuropathy, or pain, the compounds of the
present invention are administered at a dosage and for a time
sufficient to treat the symptom or condition.
[0071] For example, for a patient, compounds of formula I, or a
pharmaceutically acceptable salt thereof, may be administered,
preferably, at a dosage of from about 0.1 mg/day to about 1500
mg/day, dosed one or two times daily, more preferably from about 1
mg/day to about 200 mg/day and most preferably from about 1 mg/day
to 100 mg/day for a time sufficient to reduce and/or substantially
eliminate the number and/or severity of hot flushes or symptom or
condition of the sexual dysfunction, gastrointestinal disorder,
genitourinary disorder, chronic fatigue syndrome, fibromyalgia
syndrome, depression disorder, diabetic neuropathy, or pain.
[0072] The terms "component," "composition," "composition of
compounds," "compound," "drug," or "pharmacologically active agent"
or "active agent" or "medicament" are used interchangeably herein
to refer to a compound or compounds or composition of matter which,
when administered to a subject (human or animal) induces a desired
pharmacological and/or physiologic effect by local and/or systemic
action.
[0073] The term "modulation" refers to the capacity to either
enhance or inhibit a functional property of a biological activity
or process; for example, receptor binding or signaling activity.
Such enhancement or inhibition may be contingent on the occurrence
of a specific event, such as activation of a signal transduction
pathway and/or may be manifest only in particular cell types. The
modulator is intended to comprise any compound; e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein, and
is preferably small molecule, or peptide.
[0074] As used herein, the term "inhibitor" refers to any agent
that inhibits, suppresses, represses, or decreases a specific
activity, such as norepinephrine reuptake activity. The term
"inhibitor" is intended to comprise any compound; e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein
(preferably small molecule or peptide) that exhibits a partial,
complete, competitive and/or inhibitory effect on mammalian
(preferably the human) norepinephrine reuptake or both serotonin
reuptake and the norepinephrine reuptake, thus diminishing or
blocking (preferably diminishing) some or all of the biological
effects of endogenous norepinephrine reuptake or of both serotonin
reuptake and the norepinephrine reuptake.
[0075] Within the present invention, the compounds of formula I,
may be prepared in the form of pharmaceutically acceptable salts.
As used herein, the term "pharmaceutically acceptable salts" refers
to salts prepared from pharmaceutically acceptable non-toxic acids,
including inorganic salts and organic salts. Suitable non-organic
salts include inorganic and organic acids such as acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most
preferred is the hydrochloride salt.
[0076] "Administering," as used herein, means either directly
administering a compound or composition of the present invention,
or administering a prodrug, derivative or analog which will form an
equivalent amount of the active compound or substance within the
body.
[0077] The term "subject" or "patient" refers to an animal
including the human species that is treatable with the compounds,
compositions, and/or methods of the present invention. The term
"subject" or "subjects" is intended to refer to both the male and
female gender unless one gender is specifically indicated.
Accordingly, the term "patient" comprises any mammal which may
benefit from treatment or prevention of a disease or disorder, such
as a human, especially if the mammal is female, either in the
pre-menopausal, peri-menopausal, or post-menopausal period.
Furthermore, the term patient includes female animals including
humans and, among humans, not only women of advanced age who have
passed through menopause but also women who have undergone
hysterectomy or for some other reason have suppressed estrogen
production, such as those who have undergone long-term
administration of corticosteroids, suffer from Cushing's syndrome
or have gonadal dysgenesis. However, the term "patient" is not
intended to be limited to a woman.
[0078] "Side effect" refers to a consequence other than the one(s)
for which an agent or measure is used, as one or more adverse
effects produced by a drug, especially on a tissue or organ system
other then the one sought to be benefited by its administration. In
the case, for example, of high doses of NRIs or NRI/SRI compounds
alone, the term "side effect" may refer to such conditions as, for
example, vomiting, nausea, sweating, and hot flushes (Janowsky, et
al., Journal of Clinical Psychiatry, 1984, 45(10 Pt 2): 3-9).
[0079] "Vasomotor symptoms," (also called "vasomotor instability
symptoms" and "vasomotor disturbances") include, but are not
limited to, hot flushes (flushes), insomnia, sleep disturbances,
mood disorders, irritability, excessive perspiration, night sweats,
fatigue, and the like, caused by, inter alia, thermoregulatory
dysfunction.
[0080] The term "hot flush" (sometimes called "hot flash") is an
art-recognized term that refers to an episodic disturbance in body
temperature typically consisting of a sudden skin flushing, usually
accompanied by perspiration in a subject.
[0081] The terms "premature menopause" or "artificial menopause"
refer to ovarian failure of unknown cause that may occur before age
40. It may be associated with smoking, living at high altitude, or
poor nutritional status. Artificial menopause may result from
oophorectomy, chemotherapy, radiation of the pelvis, or any process
that impairs ovarian blood supply.
[0082] The term "pre-menopausal" means before the menopause, the
term "peri-menopausal" means during the menopause and the term
"post-menopausal" means after the menopause. "Ovariectomy" means
removal of an ovary or ovaries and can be effected according to
Merchenthaler et al., Maturitas, 1998, 30(3): 307-316.
[0083] The term "sexual dysfunction" includes, but is not limited
to, conditions relating to disorders of sexual desire and/or
arousal.
[0084] As used herein, "gastrointestinal and genitourinary
disorders" includes irritable bowel syndrome, symptomatic GERD,
hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest
pain, biliary dyskinesia, sphincter of Oddi dysfunction,
incontinence (i.e., urge incontinence, stress incontinence, genuine
stress incontinence, and mixed incontinence, including the
involuntary voiding of feces or urine, and dribbling or leakage or
feces or urine which may be due to one or more causes including but
not limited to pathology altering sphincter control, loss of
cognitive function, overdistention of the bladder, hyperreflexia
and/or involuntary urethral relaxation, weakness of the muscles
associated with the bladder or neurologic abnormalities),
interstitial cystitis (irritable bladder), and chronic pelvic pain
(including, but not limited to vulvodynia, prostatodynia, and
proctalgia).
[0085] As used herein, "chronic fatigue syndrome" (CFS) is a
condition characterized by physiological symptoms selected from
weakness, muscle aches and pains, excessive sleep, malaise, fever,
sore throat, tender lymph nodes, impaired memory and/or mental
concentration, insomnia, disordered sleep, localized tenderness,
diffuse pain and fatigue, and combinations thereof, whether or not
correlated with Epstein-Barr virus infection.
[0086] As used herein, "fibromyalgia syndrome" (FMS) includes FMS
and other somatoform disorders, including FMS associated with
depression, somatization disorder, conversion disorder, pain
disorder, hypochondriasis, body dysmorphic disorder,
undifferentiated somatoform disorder, and somatoform NOS. FMS and
other somatoform disorders are accompanied by physiological
symptoms selected from a generalized heightened perception of
sensory stimuli, abnormalities in pain perception in the form of
allodynia (pain with innocuous stimulation), abnormalities in pain
perception in the form of hyperalgesia (increased sensitivity to
painful stimuli), and combinations thereof.
[0087] As used herein, the term "depression disorder" includes
major depressive disorder, generalized anxiety disorder, panic
disorder, attention deficit disorder with or without hyperactivity,
sleep disturbance, social phobia, and combinations thereof.
[0088] The compounds of the present invention can also be used to
treat a cognitive disorder or an endogenous behavioral disorder. As
used herein, a "cognitive disorder" includes changes or defects in
alertness; mild cognitive impairment (MCI), characterized by
problems with memory, language, or other mental functions which is
severe enough to be noticeable or be detected by tests, but not
serious enough to significantly interfere with daily life;
cognitive disorder NOS (not otherwise specified), characterized by
a syndrome of cognitive impairment that does not meet the criteria
for delerium, dementia or amnesic disorders; age-related cognitive
decline (ARCD); and cognitive arousal (such as increased arousal
states). A cognition disorder can be ideopathic, or can be caused
by a variety of other factors such as a congenital defect, alcohol
or drug addiction, transient or permanent pharmacologic effects of
drugs, organic or infectious disease (e.g., Alzheimer's disease,
Parkinson's disease, AIDS), trauma (e.g., brain injury, stroke) or
advanced age. As used herein, an "endogenous behavioral disorder"
includes attention deficit disorder/attention deficit hyperactivity
disorder (ADD/ADHD, including adult and pediatric forms of
predominantly inattentive, predominantly hyperactive, or combined
types), obsessive-compulsive disorder (OCD), oppositional or
oppositional explosive defiant disorder (ODD/OEDD), anxiety and
panic disorders (APD) and temper, rage and outburst behavior
disorder (TROBD).
[0089] As used herein, "pain" includes both acute and chronic
nociceptic or neuropathic pain, which includes centralized pain,
peripheral pain, or combination thereof. The term includes many
different types of pain, including, but not limited to, visceral
pain, musculoskeletal pain, bony pain, cancer pain, inflammatory
pain, and combinations thereof, such as lower back pain, atypical
chest pain, headache such as cluster headache, migraine, herpes
neuralgia, phantom limb pain, pelvic pain, myofascial face pain,
abdominal pain, neck pain, central pain, dental pain, opioid
resistant pain, visceral pain, surgical pain, bone injury pain,
pain during labor and delivery, pain resulting from burns, post
partum pain, angina pain, peripheral neuropathy and diabetic
neuropathy, post-operative pain, and pain which is co-morbid with
nervous system disorders described herein.
[0090] As used herein, the term "acute pain" refers to centralized
or peripheral pain that is intense, localized, sharp, or stinging,
and/or dull, aching, diffuse, or burning in nature and that occurs
for short periods of time.
[0091] As used herein, the term "chronic pain" refers to
centralized or peripheral pain that is intense, localized, sharp,
or stinging, and/or dull, aching, diffuse, or burning in nature and
that occurs for extended periods of time (i.e., persistent and/or
regularly reoccurring), including, for the purposes of the present
invention, neuropathic pain and cancer pain. Chronic pain includes
neuropathic pain, hyperalgesia, and/or allodynia.
[0092] As used herein, the term "neuropathic pain" refers to
chronic pain caused by damage to or pathological changes in the
peripheral or central nervous systems. Examples of pathological
changes related to neuropathic pain include prolonged peripheral or
central neuronal sensitization, central sensitization related
damage to nervous system inhibitory and/or exhibitory functions and
abnormal interactions between the parasympathetic and sympathetic
nervous systems. A wide range of clinical conditions may be
associated with or form the basis for neuropathic pain including,
for example, diabetes, post traumatic pain of amputation (nerve
damage cause by injury resulting in peripheral and/or central
sensitization such as phantom limb pain), lower back pain, cancer,
chemical injury, toxins, other major surgeries, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, or viral or bacterial infections such as
shingles or human immunodeficiency virus (HIV), and combinations
thereof. Also included in the definition of neuropathic pain is a
condition secondary to metastatic infiltration, adiposis dolorosa,
burns, central pain conditions related to thalamic conditions, and
combinations thereof.
[0093] As used herein, the term "hyperalgesia" refers to pain where
there is an increase in sensitivity to a typically noxious
stimulus.
[0094] As used herein, the term "allodynia" refers to an increase
in sensitivity to a typically non-noxious stimulus.
[0095] As used herein, the term "visceral pain" refers to pain
associated with or resulting from maladies of the internal organs,
such as, for example, ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, and combinations thereof.
[0096] As used herein, the term "female-specific pain" refers to
pain that may be acute and/or chronic pain associated with female
conditions. Such groups of pain include those that are encountered
solely or predominately by females, including pain associated with
menstruation, ovulation, pregnancy or childbirth, miscarriage,
ectopic pregnancy, retrograde menstruation, rupture of a follicular
or corpus luteum cyst, irritation of the pelvic viscera, uterine
fibroids, adenomyosis, endometriosis, infection and inflammation,
pelvic organ ischemia, obstruction, intra-abdominal adhesions,
anatomic distortion of the pelvic viscera, ovarian abscess, loss of
pelvic support, tumors, pelvic congestion or referred pain from
non-gynecological causes, and combinations thereof.
[0097] "Alkyl," as used herein, refers to an optionally
substituted, saturated straight, branched, or cyclic hydrocarbon
having from about 1 to about 20 carbon atoms (and all combinations
and subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 1 to about 8 carbon atoms or 1 to 6
carbon atoms (C.sub.1-C.sub.6) being preferred, and with from about
1 to about 4 carbon atoms, herein referred to as "lower alkyl",
being more preferred. Alkyl groups include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, cyclopentyl, cyclopropyl, isopentyl, neopentyl, n-hexyl,
isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl,
2,2-dimethylbutyl, and 2,3-dimethylbutyl. A branched alkyl group
has at least 3 carbon atoms (e.g., an isopropyl group), and in
various embodiments, has up to 6 carbon atoms, i.e., a branched
lower alkyl group. A branched alkyl group has at least 3 carbon
atoms (e.g., an isopropyl group), and in various embodiments, has
up to 6 carbon atoms, i.e., a branched lower alkyl group. Examples
of branched lower alkyl groups include, but are not limited to:
##STR00010##
[0098] "Alkenyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more double bonds, wherein
alkyl is as defined herein. Preferred alkenyl groups have from 2 to
6 carbon atoms (C.sub.2-C.sub.6). Alkenyl groups can be optionally
substituted.
[0099] "Alkynyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more triple bonds, wherein
alkyl is as defined herein. Preferred alkynyl groups have from 2 to
6 carbon atoms (C.sub.2-C.sub.6). Alkynyl groups can be optionally
substituted.
[0100] "Alkylenyl", "alkenylenyl", "alkynylenyl", and "arylenyl"
refer to the subsets of alkyl, alkenyl, alkynyl and aryl groups,
respectively, as defined herein, including the same residues as
alkyl, alkenyl, alkynyl, and aryl but having two points of
attachment within a chemical structure. Examples of
C.sub.1-C.sub.6alkylenyl include methylenyl (--CH.sub.2--),
ethylenyl (--CH.sub.2CH.sub.2--), propylenyl
(--CH.sub.2CH.sub.2CH.sub.2--), and dimethylpropylenyl
(--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--). Likewise, examples of
C.sub.2-C.sub.6alkenylenyl include ethenylenyl (--CH.dbd.CH-- and
propenylenyl (--CH.dbd.CH--CH.sub.2--). Examples of
C.sub.2-C.sub.6alkynylenyl include ethynylenyl (--C.ident.C--) and
propynylenyl (--C.ident.C--CH.sub.2--).
[0101] Examples of arylenyl groups include phenylenyl;
##STR00011##
Preferably, arylenyl groups contain 6 carbon atoms (C.sub.6).
[0102] "Halo," as used herein, refers to chloro, bromo, fluoro, and
iodo.
[0103] "Aryl" as used herein, refers to an optionally substituted,
mono-, di-, tri-, or other multicyclic aromatic ring system having
from about 5 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 10 carbons (C.sub.6-C.sub.10)
being preferred. Non-limiting examples include, for example,
phenyl, naphthyl, anthracenyl, and phenanthrenyl.
[0104] "Heteroaryl," as used herein, refers to an optionally
substituted, mono-, di-, tri-, or other multicyclic aromatic ring
system that includes at least one, and preferably from 1 to about 4
heteroatom ring members selected from sulfur, oxygen and nitrogen.
Heteroaryl groups can have, for example, from about 3 to about 50
carbon atoms (and all combinations and subcombinations of ranges
and specific numbers of carbon atoms therein), with from about 4 to
about 10 carbons being preferred. Non-limiting examples of
heteroaryl groups include, for example, pyrryl, furyl, pyridyl,
1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,
thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
[0105] "Heterocyclic ring," as used herein, refers to a stable 4-
to 12-membered monocyclic or bicyclic or 7- to 10-membered bicyclic
heterocyclic ring that is saturated, partially unsaturated or
unsaturated (aromatic), and which contains carbon atoms and from 1
to 4 heteroatoms independently selected from the group consisting
of N, O and S and including any bicyclic group in which any of the
above defined heterocyclic rings is fused to a benzene ring. The
nitrogen and sulfur heteroatoms may optionally be oxidized. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. If
specifically noted, a nitrogen atom in the heterocycle may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocycle exceeds one, then these
heteroatoms are not adjacent to one another. It is preferred that
the total number of S and O atoms in the heterocycle is not more
than two. Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl,
.alpha.-, .beta.-, or .gamma.-carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles
include, but are not limited to, pyridinyl, furanyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl,
1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,
oxindolyl, benzoxazolinyl, or isatinyl. Also included are fused
ring and spiro compounds containing, for example, the above
heterocycles.
[0106] "Alkoxy," as used herein, refers to the group R--O-- where R
is an alkyl group, as defined herein. Preferred alkoxy groups have
from 1 to 6 carbon atoms (C.sub.1-C.sub.6).
[0107] "Arylalkyl," as used herein, refers to the group R'--R--
where R' is an aryl group, as defined herein, and R is an alkyl
group, as defined herein. Preferred arylalkyl groups have from 7 to
16 carbon atoms (C.sub.7-C.sub.16).
[0108] "Heteroarylalkyl," as used herein, refers to the group
R''-R-- where R'' is a heteroaryl group, as defined herein, and R
is an alkyl group, as defined herein.
[0109] "Heteroarylmethyl," as used herein, refers to the group
R''--CH.sub.2-- where R'' is a heteroaryl group, as defined
herein.
[0110] "Alkanoyloxy," as used herein, refers to the group
R--C(.dbd.O)--O-- where R is an alkyl group, as defined herein, of
1 to 5 carbon atoms (C.sub.1-C.sub.5).
[0111] "Alkylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R', where R' is alkyl, as defined herein.
Preferred alkysulfoxide groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0112] "Arylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R', where R' is aryl, as defined herein.
Preferred arylsulfoxide groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0113] "Alkylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R', where R' is alkyl, as defined herein.
Preferred alkylsulfone groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0114] "Arylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R', where R' is aryl, as defined herein.
Preferred arylsulfone groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0115] "Alkylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R, where each R is independently, alkyl, as
defined above, or the NR part may also be NH. Preferred
alkylsulfonamide groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0116] "Arylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R', where R is H or alkyl, as defined
herein, and R' is aryl, as defined herein. Preferred
arylsulfonamide groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0117] "Heteroarylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R'', where R is H or alkyl, as defined
herein, and R'' is aryl, as defined herein.
[0118] "Alkylamido," as used herein, refers to --NR--C(.dbd.O)--R',
where each R is independently, alkyl, as defined above, or the NR
part may also be NH. Preferred alkylamido groups have from 1 to 6
carbon atoms (C.sub.1-C.sub.6).
[0119] "Arylamido," as used herein, refers to --NR--C(.dbd.O)--R'',
where R is H or alkyl, as defined herein, and R'' is aryl, as
defined herein. Preferred arylamido groups have from 6 to 10 carbon
atoms (C.sub.6-C.sub.10).
[0120] "Phenylamido," as used herein, refers to
--NR--C(.dbd.O)-phenyl, where R is H or alkyl, as defined
above.
[0121] As used herein, the terms "optionally substituted" or
"substituted or unsubstituted" are intended to refer to the
optional replacement of up to four hydrogen atoms with up to four
independently selected substituent groups as defined herein. Unless
otherwise specified, suitable substituent groups independently
include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl,
aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl,
formyl, alkyl, perfluoroalkyl, alkylamino, dialkylamino, alkoxy,
alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, aryl,
heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl,
carboxyalkyl, haloalkyl, alkenyl, alkynyl, arylalkyl, aryloxy,
heteroaryloxy, heteroarylalkyl, and the like. Substituent groups
that have one or more available hydrogen atoms can in turn
optionally bear further independently selected substituents, to a
maximum of three levels of substitutions. For example, the term
"optionally substituted alkyl" is intended to mean an alkyl group
that can optionally have up to four of its hydrogen atoms replaced
with substituent groups as defined above (i.e., a first level of
substitution), wherein each of the substituent groups attached to
the alkyl group can optionally have up to four of its hydrogen
atoms replaced by substituent groups as defined above (i.e., a
second level of substitution), and each of the substituent groups
of the second level of substitution can optionally have up to four
of its hydrogen atoms replaced by substituent groups as defined
above (i.e., a third level of substitution).
[0122] Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming the
terminal portion of the functionality followed by the adjacent
functionality toward the point of attachment. For example, the
substituent "arylalkoxycabonyl" refers to the group
(aryl)-(alkyl)-O--C(O)--.
[0123] It is understood that the above definitions are not intended
to include impermissible substitution patterns (e.g., methyl
substituted with 5 fluoro groups). Such impermissible substitution
patterns are well known to the skilled artisan.
[0124] At various places in the present specification, substituents
of compounds are disclosed in groups or in ranges. It is
specifically intended that the description include each and every
individual subcombination of the members of such groups and ranges.
For example, the term "C.sub.1-6 alkyl" is specifically intended to
individually disclose C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.1-C.sub.6, C.sub.1-C.sub.5, C.sub.1-C.sub.4,
C.sub.1-C.sub.3, C.sub.1-C.sub.2, C.sub.2-C.sub.6, C.sub.2-C.sub.5,
C.sub.2-C.sub.4, C.sub.2-C.sub.3, C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.6, C.sub.4-C.sub.5, and
C.sub.5-C.sub.6 alkyl. By way of another example, the term "5-9
membered heteroaryl group" is specifically intended to individually
disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7,
5-6, 6-9, 6-8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
[0125] The term "protecting group" or "G.sub.p" with respect to
amine groups, hydroxyl groups and sulfhydryl groups refers to forms
of these functionalities which are protected from undesirable
reaction with a protecting group known to those skilled in the art,
such as those set forth in Protective Groups in Organic Synthesis,
Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York,
N.Y., (3rd Edition, 1999) which can be added or removed using the
procedures set forth therein. Examples of protected hydroxyl groups
include, but are not limited to, silyl ethers such as those
obtained by reaction of a hydroxyl group with a reagent such as,
but not limited to, t-butyldimethyl-chlorosilane,
trimethylchlorosilane, triisopropylchlorosilane,
triethylchlorosilane; substituted methyl and ethyl ethers such as,
but not limited to methoxymethyl ether, methylthiomethyl ether,
benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl
ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether,
benzyl ether; esters such as, but not limited to, benzoylformate,
formate, acetate, trichloroacetate, and trifluoracetate. Examples
of protected amine groups include, but are not limited to, amides
such as, formamide, acetamide, trifluoroacetamide, and benzamide;
carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB,
benzyl, and dithiosuccinimide; and others. Examples of protected or
capped sulfhydryl groups include, but are not limited to,
thioethers such as S-benzyl thioether, and S-4-picolyl thioether;
substituted S-methyl derivatives such as hemithio, dithio and
aminothio acetals; and others.
[0126] Reference to "activated" or "an activating group" or
"G.sub.a" as used herein indicates having an electrophilic moiety
bound to a substituent, capable of being displaced by a
nucleophile. Examples of preferred activating groups are halogens,
such as Cl, Br or I, and F; triflate; mesylate, or tosylate;
esters; aldehydes; ketones; epoxides; and the like. An example of
an activated group is acetylchloride, which is readily attacked by
a nucleophile, such as piperidine group to form a
N-acetylpiperidine functionality.
[0127] The term "deprotecting" refers to removal of a protecting
group, such as removal of a benzyl or BOC group bound to an amine.
Deprotecting may be preformed by heating and/or addition of
reagents capable of removing protecting groups. In preferred
embodiments, the deprotecting step involves addition of an acid,
base, reducing agent, oxidizing agent, heat, or any combination
thereof. One preferred method of removing BOC groups from amino
groups is to add HCl in ethyl acetate. Many deprotecting reactions
are well known in the art and are described in Protective Groups in
Organic Synthesis, Greene, T. W., John Wiley & Sons, New York,
N.Y., (1st Edition, 1981), the entire disclosure of which is herein
incorporated by reference.
[0128] One aspect of the invention provides a compound of formula
I:
##STR00012## [0129] or a tautomer or pharmaceutically acceptable
salt thereof; [0130] wherein: [0131] n is an integer from 0 to 4;
[0132] m is an integer from 1 to 6; [0133] X is --CH.sub.2--;
[0134] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or
arylamido; wherein each aryl or heteroaryl is independently
substituted with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups;
and each arylsulfonamide or arylamido is independently substituted
with 0-3 alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido groups; [0135]
R.sup.2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl
optionally substituted with alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; [0136] R.sup.3 and R.sup.4 are, independently, H, alkyl,
arylalkyl or heteroarylmethyl, wherein each of alkyl, arylalkyl or
heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl groups, provided that neither [0137] R.sup.3 or
R.sup.4 contain an aminoalkyl group; [0138] represents an S-isomer,
R-isomer or racemate; and [0139] wherein 1-3 carbon atoms in ring A
may optionally be replaced with N.
[0140] In another embodiment, each R.sup.1 is H.
[0141] In another embodiment, R.sup.2 is:
##STR00013##
[0142] wherein,
[0143] each R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
independently selected from the group consisting of H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, or arylamido.
[0144] In another embodiment, R.sup.9 is F. In another embodiment,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are H. In another embodiment
R.sup.5 is H or F, R.sup.6 is H or F, R.sup.7 is H or F, R.sup.8 is
H or F and R.sup.9 is H or F. In another embodiment, R.sup.5,
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are H, halo, alkyl or
alkoxy.
[0145] In another embodiment, R.sup.3 is alkyl. More particularly,
methyl.
[0146] In another embodiment, R.sup.4 is H.
[0147] In another embodiment, m is an integer from 2 to 6. More
particularly, m is 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4,
2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, or 4 to 5. In another
embodiment, m is 1, m is 2, m is 3, m is 4, m is 5 or m is 6.
[0148] In another embodiment, ring A comprises all carbon
atoms.
[0149] In another embodiment, R.sup.2 is pyridinyl,
methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or
quinolinyl.
[0150] In another embodiment, R.sup.2 is phenyl, fluoro-phenyl,
difluoro-phenyl, trifluoro-phenyl, chloro-phenyl,
fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl
trifluoromethoxy-phenyl, methyl-fluoro-phenyl,
methoxy-fluoro-phenyl, or naphthyl.
[0151] In another embodiment, represents an S-isomer.
Alternatively, represents an R-isomer. Alternatively, represents a
racemate.
[0152] In another embodiment: [0153] R.sup.1 is H; [0154] R.sup.9
is F; [0155] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are H; [0156]
R.sup.3 is methyl; [0157] R.sup.4 is H; [0158] m is 2; and [0159]
represents an S-isomer.
[0160] In another embodiment, the compound is selected from the
group consisting of:
##STR00014## ##STR00015## ##STR00016## ##STR00017##
[0161] Another aspect of the invention provides a compound selected
from the group consisting of: [0162]
1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
butan-2-ol; [0163]
(2R)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol; [0164]
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol; [0165]
3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl}phenol: [0166]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol; [0167]
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)pentan-2-ol; [0168]
(2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]butan-2-ol; [0169]
(2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)pentan-2-ol; [0170]
(2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)pentan-2-ol; [0171]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)but-
an-2-ol; [0172]
1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
butan-2-ol; [0173]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino-
)butan-2-ol; [0174]
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)--
yl)butan-2-ol; [0175]
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-ol; [0176]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)bu-
tan-2-ol; [0177]
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylami-
no)butan-2-ol; [0178]
(2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H-
)-yl)butan-2-ol; [0179]
(2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H-
)-yl)butan-2-ol; [0180]
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropyl-
amino)butan-2-ol; [0181]
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropyl-
amino)butan-2-ol; [0182]
(2S)-1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1-
(3H)-yl)butan-2-ol; [0183]
(2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(-
3H)-yl)butan-2-ol; [0184]
(2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(-
3H)-yl)butan-2-ol; [0185]
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamin-
o)butan-2-ol; [0186]
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamin-
o)butan-2-ol; [0187]
(2S)-1-(cyclopropylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol; [0188]
(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol; [0189]
(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol; [0190]
(2S)-1-(cyclopropylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol; [0191]
(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol; [0192]
(2S)-1-(cyclopropylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzot-
hiadiazol-1(3H)-yl]butan-2-ol; [0193]
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylami-
no)butan-2-ol; [0194]
(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0195]
(2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0196]
(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0197]
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0198]
(2S)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol; [0199]
(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]butan-2-ol; [0200]
(2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol; [0201]
(2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol; [0202]
(2R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0203]
(2R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0204]
(2R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0205]
(2R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol; [0206]
(2R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol; [0207]
(2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]butan-2-ol; [0208]
(2R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol; [0209]
(2R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol; [0210]
(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol; [0211]
(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol; [0212]
(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol; [0213]
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(isopropylamino)butan-2-ol; [0214]
(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiaz-
ol-1(3H)-yl]butan-2-ol; and
[0215] pharmaceutically acceptable salts thereof.
[0216] In another embodiment, said pharmaceutically acceptable salt
is a hydrochloride or dihydrochloride.
[0217] Another aspect of the invention provides a composition,
comprising:
[0218] a. at least one compound of formula I; and
[0219] b. at least one pharmaceutically acceptable carrier.
[0220] Another aspect of the invention provides a method for
treating or preventing a condition selected from the group
consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, endogenous
behavioral disorder, cognitive disorder, diabetic neuropathy, pain,
and combinations thereof in a subject in need thereof, comprising
the step of:
[0221] administering to said subject an effective amount of a
compound of formula I.
[0222] In certain embodiments, the vasomotor symptom is hot
flush.
[0223] In certain embodiments, the sexual dysfunction is
desire-related or arousal-related.
[0224] In certain embodiments, the gastrointestinal disorder or the
genitourinary disorder is stress incontinence or urge
incontinence.
[0225] In certain embodiments, the condition is chronic fatigue
syndrome.
[0226] In certain embodiments, the condition is fibromyalgia
syndrome.
[0227] In certain embodiments, the condition is a depression
disorder selected from the group consisting of major depressive
disorder, generalized anxiety disorder, panic disorder, attention
deficit disorder with or without hyperactivity, sleep disturbance,
social phobia, and combinations thereof.
[0228] In certain embodiments, the disorder is an endogenous
behavioral disorder or a cognitive disorder.
[0229] In certain embodiments, the condition is diabetic
neuropathy.
[0230] In certain embodiments, the condition is pain.
[0231] In certain embodiments, the pain is acute centralized pain,
acute peripheral pain, or a combination thereof.
[0232] In certain embodiments, the pain is chronic centralized
pain, chronic peripheral pain, or a combination thereof.
[0233] In certain embodiments, the pain is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain,
inflammatory pain, or a combination thereof.
[0234] In certain embodiments, the neuropathic pain is associated
with diabetes, post traumatic pain of amputation, lower back pain,
cancer, chemical injury, toxins, major surgery, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, burns, central pain
conditions related to thalamic conditions, or a combination
thereof.
[0235] In certain embodiments, the neuropathic pain is
post-herpetic neuralgia.
[0236] In certain embodiments, the visceral pain is associated with
ulcerative colitis, irritable bowel syndrome, irritable bladder,
Crohn's disease, rheumatologic (arthralgias), tumors, gastritis,
pancreatitis, infections of the organs, biliary tract disorders, or
a combination thereof.
[0237] In certain embodiments, the pain is female-specific
pain.
[0238] The present invention provides a treatment for vasomotor
symptoms by methods of recovering the reduced activity of
norepinephrine. Without wishing to be bound by any theory,
norepinephrine activity in the hypothalamus or in the brainstem can
be elevated by (i) blocking the activity of the NE transporter,
(ii) blocking the activity of the presynaptic
adrenergic.sub..alpha.2 receptor with an antagonist, or (iii)
blocking the activity of 5-HT on NE neurons with a 5-HT.sub.2a
antagonist.
[0239] The compounds of the invention are also useful to prevent
and treat pain. The pain may be, for example, acute pain or chronic
pain. The pain may also be centralized or peripheral.
[0240] Examples of pain that can be acute or chronic and that can
be treated in accordance with the methods of the present invention
include inflammatory pain, musculoskeletal pain, bony pain,
lumbosacral pain, neck or upper back pain, visceral pain, somatic
pain, neuropathic pain, cancer pain, pain caused by injury or
surgery such as burn pain or dental pain, or headaches such as
migraines or tension headaches, or combinations of these pains. One
skilled in the art will recognize that these pains may overlap one
another. For example, a pain caused by inflammation may also be
visceral or musculoskeletal in nature.
[0241] In a preferred embodiment of the present invention the
compounds useful in the present invention are administered in
mammals to treat chronic pain such as neuropathic pain associated
for example with damage to or pathological changes in the
peripheral or central nervous systems; cancer pain; visceral pain
associated with for example the abdominal, pelvic, and/or perineal
regions or pancreatitis; musculoskeletal pain associated with for
example the lower or upper back, spine, fibromyalgia,
temporomandibular joint, or myofascial pain syndrome; bony pain
associated with for example bone or joint degenerating disorders
such as osteoarthritis, rheumatoid arthritis, or spinal stenosis;
headaches such migraine or tension headaches; or pain associated
with infections such as HIV, sickle cell anemia, autoimmune
disorders, multiple sclerosis, or inflammation such as
osteoarthritis or rheumatoid arthritis.
[0242] In a more preferred embodiment, the compounds useful in this
invention are used to treat chronic pain that is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain or
inflammatory pain or combinations thereof, in accordance with the
methods described herein. Inflammatory pain can be associated with
a variety of medical conditions such as osteoarthritis, rheumatoid
arthritis, surgery, or injury. Neuropathic pain may be associated
with for example diabetic neuropathy, peripheral neuropathy,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, or nerve damage cause by injury resulting in peripheral
and/or central sensitization such as phantom limb pain, reflex
sympathetic dystrophy or postthoracotomy pain, cancer, chemical
injury, toxins, nutritional deficiencies, or viral or bacterial
infections such as shingles or HIV, or combinations thereof. The
methods of use for compounds of this invention further include
treatments in which the neuropathic pain is a condition secondary
to metastatic infiltration, adiposis dolorosa, burns, or central
pain conditions related to thalamic conditions.
[0243] As mentioned previously, the methods of the present
invention may be used to treat pain that is somatic and/or visceral
in nature. For example, somatic pain that can be treated in
accordance with the methods of the present invention include pains
associated with structural or soft tissue injury experienced during
surgery, dental procedures, burns, or traumatic body injuries.
Examples of visceral pain that can be treated in accordance with
the methods of the present invention include those types of pain
associated with or resulting from maladies of the internal organs
such as ulcerative colitis, irritable bowel syndrome, irritable
bladder, Crohn's disease, rheumatologic (arthralgias), tumors,
gastritis, pancreatitis, infections of the organs, or biliary tract
disorders, or combinations thereof. One skilled in the art will
also recognize that the pain treated according to the methods of
the present invention may also be related to conditions of
hyperalgesia, allodynia, or both. Additionally, the chronic pain
may be with or without peripheral or central sensitization.
[0244] The compounds useful in this invention may also be used to
treat acute and/or chronic pain associated with female conditions,
which may also be referred to as female-specific pain. Such groups
of pain include those that are encountered solely or predominately
by females, including pain associated with menstruation, ovulation,
pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde
menstruation, rupture of a follicular or corpus luteum cyst,
irritation of the pelvic viscera, uterine fibroids, adenomyosis,
endometriosis, infection and inflammation, pelvic organ ischemia,
obstruction, intra-abdominal adhesions, anatomic distortion of the
pelvic viscera, ovarian abscess, loss of pelvic support, tumors,
pelvic congestion or referred pain from non-gynecological
causes.
[0245] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
[0246] the process comprising:
[0247] reacting HN(R.sup.3)(R.sup.4) a compound of formula IA:
##STR00018##
[0248] wherein the compound of formula I is formed.
[0249] In another aspect of the invention, the compound of formula
IA is formed by:
[0250] activating a primary or secondary hydroxy group on the
compound of formula IB:
##STR00019## [0251] to form an activated compound of formula IB;
and [0252] contacting the activated compound of formula IB with a
base, wherein the compound of formula IA is formed.
[0253] In another embodiment, the activating step comprises:
[0254] tosylating the primary hydroxy group on the compound of
formula IB.
[0255] In another aspect of the invention, the compound of formula
IB is formed by:
[0256] deprotecting a compound of formula IC:
##STR00020##
[0257] In another embodiment, the deprotecting step comprises:
[0258] contacting the compound of formula IC with an acid.
[0259] In another embodiment, the acid is hydrochloric acid
(HCl).
[0260] In another aspect of the invention, the compound of formula
IC is prepared by:
[0261] oxidizing a compound of formula ID:
##STR00021##
[0262] In another embodiment, the oxidizing step is performed in
the presence of sodium periodate (NaIO.sub.4) and ruthenium
chloride (RuCl.sub.3).
[0263] In another aspect of the invention, the compound of formula
ID is prepared by:
[0264] reacting thionyl chloride (SOCl.sub.2) with a compound of
formula IE:
##STR00022##
[0265] In another embodiment, the reacting step is performed in the
presence of triethylamine (Et.sub.3N).
[0266] In another aspect of the invention, the compound of formula
IE is prepared by:
[0267] reacting a compound of formula IF:
##STR00023##
[0268] with a compound of formula IG:
##STR00024##
[0269] wherein, the compound of formula IE is formed.
[0270] In another embodiment, the reacting step is performed in the
presence of sodium cyanoborohydride (NaCNBH.sub.3) and acetic acid
(AcOH).
[0271] In another embodiment, the reacting step: [0272] is
performed at or above 30.degree. C.; [0273] is performed in a
protic solvent, an aprotic solvent, a polar solvent, a nonpolar
solvent, a protic polar solvent, an aprotic nonpolar solvent, or an
aprotic polar solvent; or [0274] includes a purification step
comprising at least one of: filtration, extraction, chromatography,
trituration, or recrystallization.
[0275] Some of the compounds of the present invention may contain
chiral centers and such compounds may exist in the form of
stereoisomers (i.e. enantiomers or diastereomers). The present
invention includes all such stereoisomers and any mixtures thereof
including racemic mixtures. Racemic mixtures of the stereoisomers
as well as the substantially pure stereoisomers are within the
scope of the invention. The term "substantially pure," as used
herein, refers to at least about 90 mole %, more preferably at
least about 95 mole %, and most preferably at least about 98 mole %
of the desired stereoisomer is present relative to other possible
stereoisomers. Preferred enantiomers may be isolated from racemic
mixtures by any method known to those skilled in the art, including
high performance liquid chromatography (HPLC) and the formation and
crystallization of chiral salts or prepared by methods described
herein. See, for example, Jacques, et al., Enantiomers, Racemates
and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H.,
et al., Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistry
of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S. H. Tables
of Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel,
Ed., University of Notre Dame Press, Notre Dame, IN 1972), the
entire disclosures of which are herein incorporated by
reference.
[0276] The present invention includes prodrugs of the compounds of
formula I. "Prodrug," as used herein, means a compound which is
convertible in vivo by chemical or metabolic means (e.g. by
hydrolysis) to a compound of formula I. Various forms of prodrugs
are known in the art, for example, as discussed in Bundgaard,
(ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.),
Methods in Enzymology, vol. 4, Academic Press (1985);
Krogsgaard-Larsen, et al., (ed). "Design and Application of
Prodrugs," Textbook of Drug Design and Development, Chapter 5,
113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews,
1992, 8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988,
77:285 et seq.; and Higuchi and Stella (eds.) Prodrugs as Novel
Drug Delivery Systems, American Chemical Society (1975), the entire
disclosures of which are herein incorporated by reference.
[0277] Further, the compounds of formula I may exist in unsolvated
as well as in solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the
solvated forms are considered equivalent to the unsolvated forms
for the purpose of the present invention.
[0278] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art. The
compounds can be synthesized, for example, by the methods described
below, or variations thereon as appreciated by the skilled artisan.
All processes disclosed in association with the present invention
are contemplated to be practiced on any scale, including milligram,
gram, multigram, kilogram, multikilogram or commercial industrial
scale.
[0279] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Protecting groups that may be
employed in accordance with the present invention may be described
in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic
Synthesis 2d. Ed., Wiley & Sons, 1991, the entire disclosure of
which is herein incorporated by reference.
[0280] Compounds of the present invention are suitably prepared in
accordance with the following general description and specific
examples. Variables used are as defined for formula I, unless
otherwise noted. The reagents used in the preparation of the
compounds of this invention can be either commercially obtained or
can be prepared by standard procedures described in the literature.
In accordance with this invention, compounds of formula I may be
produced by the following reaction schemes (Schemes 1-3).
[0281] The compounds of this invention contain chiral centers,
providing for various stereoisomeric forms such as diastereomeric
mixtures, enantiomeric mixtures as well as optical isomers. The
individual optical isomers can be prepared directly through
asymmetric and/or stereospecific synthesis or by conventional
chiral separation of optical isomers from the enantiomeric
mixture.
##STR00025## ##STR00026##
[0282] Following Scheme 1, an appropriate fluoronitroarene 1 may be
substituted with an aryl amine using a base under standard
conditions to provide an aminonitroarene 2. Typically conditions
for this reaction a base such as sodium hydride in DMF or an
organometallic base such as butyllithium in THF. Reduction of the
nitro group in structure 2 is accomplished under standard
conditions using hydrogen and a suitable catalyst such as palladium
or Raney nickel to provide a dianiline 3. Nitro reduction is a
common transformation and one could employ a number of alternative
procedures including reduction conditions using metal salts such as
aqueous HCl with tin(II) chloride or aqueous ammonium chloride with
zinc metal. The dianiline 3 is then treated a suitable sulfate
containing reagent to form arylsulfamide of structure 4. In a
typical example, 3 was heated with sulfamide in diglyme to provide
the cyclized product 4. The acidic nitrogen is then combined with a
suitably substituted side chain providing products 5 or 6 defending
on the structure of the desired side chain. An effective method for
attaching the side chain to sulfamide 4 is the Mitsunobu reaction
in which an alcohol is activated and displaced by treating with a
phosphine and an activating reagent. In accordance with the
embodiment of the invention, typical conditions for effecting the
attachment of the sulfamide to the alcohol containing side chain
were treatment with diisopropyl azodicarboxylate and
triphenylphosphine in THF. Another suitable method for
accomplishing side chain attachment is direct nucleophilic
substitution of a leaving group containing side chain with the
sulfamide and can be facilitated by addition of a base in a
suitable solvent. Typically compounds of structure 5 with a bromine
containing side chain were treated with an excess of the desired
amine to provide the desired compounds of formula I. An alternative
method for the synthesis of compounds of formula I is possible from
6 where the side chain is attached with the amine present in
protected form (the protecting group is represented by the letter
P). Any suitable amine protecting group, t-butoxycarbonyl in a
typical example, may be used. The protecting group is then removed,
in the case of t-butoxycarbonyl using an acid such as hydrochloric
acid, to give compounds of formula I.
##STR00027## ##STR00028##
[0283] An additional method for the synthesis of compounds of
formula I is described in Scheme 2. An appropriate fluoronitroarene
is substituted with an amine bearing the desired side chain to give
compounds of structure 7. Reduction of the nitro group under
conditions described in Scheme 1 provides 8. Compounds of structure
8 can be converted to arylsulfamide of structure 9 by treatment
with a suitable sulfate containing reagent. In a typical example, 8
was heated with sulfamide in diglyme to provide the cyclized
product 9. An aryl group may then be attached to the sulfamide 9
using conventional methods for formation of an aryl-nitrogen bond.
In a typical example an aryl boronic acid forms an aryl-nitrogen
bond in the presence of a transition metal salt such as copper(II)
acetate to provide 6. Subsequent deprotection of the protecting
group P in 6 affords compounds of formula I. As described in Scheme
1, the protecting group t-butoxycarbonyl was useful for this
purpose and is readily removed using an acid such as hydrochloric
acid to give compounds of formula I.
##STR00029## ##STR00030##
[0284] Following Scheme 3, dianiline 3 can be treated with an
aldehyde using standard reductive amination conditions giving
substituted dianiline 11. Condensation of this with thionyl
chloride under basic conditions gives the sulfonylurea 12 which can
be readily oxidized utilizing a variety of conditions to the
sulfamide 13. Treatment of this with hydrogen chloride unmasks the
diol 14 which is converted to the tosylate 15 under basic
conditions. When treated with potassium carbonate this is readily
converted to the epoxide 16 which can be treated with an excess of
the desired amine to provide the desired compounds of formula
17.
Scheme 4
[0285] Following Scheme 4, sulfamide 4, prepared as in Scheme 1,
can be readily alkylated with an epoxide containing a leaving group
including but not limited to bromide, tosylate or mesylate
providing compounds of structure 16. Typically compounds of
structure 16 were treated with an excess of the desired amine to
provide the desired compounds of formula 1.
[0286] In other embodiments, the invention is directed to
pharmaceutical compositions, comprising: [0287] a. at least one
compound of formula I, or pharmaceutically acceptable salt thereof;
and [0288] b. at least one pharmaceutically acceptable carrier.
[0289] Generally, the compound of formula I, or a pharmaceutically
acceptable salt thereof, will be present at a level of from about
0.1%, by weight, to about 90% by weight, based on the total weight
of the pharmaceutical composition, based on the total weight of the
pharmaceutical composition. Preferably, the compound of formula I,
or a pharmaceutically acceptable salt thereof, will be present at a
level of at least about 1%, by weight, based on the total weight of
the pharmaceutical composition. More preferably, the compound of
formula I, or a pharmaceutically acceptable salt thereof, will be
present at a level of at least about 5%, by weight, based on the
total weight of the pharmaceutical composition. Even more
preferably, the compound of formula I, or a pharmaceutically
acceptable salt thereof will be present at a level of at least
about 10%, by weight, based on the total weight of the
pharmaceutical composition. Yet even more preferably, the compound
of formula I, or a pharmaceutically acceptable salt thereof, will
be present at a level of at least about 25%, by weight, based on
the total weight of the pharmaceutical composition.
[0290] Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's
Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro,
Mack Publishing Company, Easton, Pa. (1985), the entire disclosure
of which is herein incorporated by reference. Pharmaceutically
acceptable carriers are those that are compatible with the other
ingredients in the formulation and biologically acceptable.
[0291] The compounds of this invention may be administered orally
or parenterally, neat or in combination with conventional
pharmaceutical carriers. Applicable solid carriers can include one
or more substances that may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or an
encapsulating material. In powders, the carrier is a finely divided
solid that is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to about 99% of the
active ingredient. Suitable solid carriers include, for example,
calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin, starch, gelatin, cellulose, methyl cellulose, sodium
carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes
and ion exchange resins.
[0292] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups, and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers, or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
[0293] Liquid pharmaceutical compositions for parenteral
administration, which are sterile solutions or suspensions, can be
administered by, for example, intramuscular, intraperitoneal or
subcutaneous injection. Sterile solutions can also be administered
intravenously. Oral administration may be either liquid or solid
composition form.
[0294] Preferably the pharmaceutical composition is in unit dosage
form, e.g. as tablets, capsules, powders, solutions, suspensions,
emulsions, granules, or suppositories. In such form, the
composition is sub-divided in unit dose containing appropriate
quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example packeted powders, vials,
ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself,
or it can be the appropriate number of any such compositions in
package form.
[0295] In another embodiment of the present invention, the
compounds useful in the present invention may be administered to a
mammal with one or more other pharmaceutical active agents such as
those agents being used to treat any other medical condition
present in the mammal. Examples of such pharmaceutical active
agents include pain relieving agents, anti-angiogenic agents,
anti-neoplastic agents, anti-diabetic agents, anti-infective
agents, or gastrointestinal agents, or combinations thereof.
[0296] The one or more other pharmaceutical active agents may be
administered in a therapeutically effective amount simultaneously
(such as individually at the same time, or together in a
pharmaceutical composition), and/or successively with one or more
compounds of the present invention.
[0297] The term "combination therapy" refers to the administration
of two or more therapeutic agents or compounds to treat a
therapeutic condition or disorder described in the present
disclosure, for example hot flush, sweating,
thermoregulatory-related condition or disorder, or other condition
or disorder. Such administration includes use of each type of
therapeutic agent in a concurrent manner. In either case, the
treatment regimen will provide beneficial effects of the drug
combination in treating the conditions or disorders described
herein.
[0298] The route of administration may be any enteral or parenteral
route which effectively transports the active compound of formula
I, or a pharmaceutically acceptable salt thereof, to the
appropriate or desired site of action; such as oral, nasal,
pulmonary, transdermal, such as passive or iontophoretic delivery,
or parenteral, e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intrathecal, intra-articular,
intranasal, ophthalmic solution or an ointment. Furthermore, the
administration of compound of formula I, or pharmaceutically
acceptable salt thereof, with other active ingredients may be
separate, consecutive or simultaneous.
[0299] The present invention is further defined in the following
Examples, in which all parts and percentages are by weight and
degrees are Celsius, unless otherwise stated. It should be
understood that these examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only. From the above discussion and these examples, one skilled in
the art can ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions.
EXAMPLES
Example 1, 2, and 3
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methy-
lamino)butan-2-ol
##STR00031##
[0301] Step 1:
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.45 g, 1.7 mmol) was dissolved in tetrahydrofuran (20 mL) and
triphenylphosphine (0.54 g, 2 mmol) was added followed by
3-buten-1-ol (0.16 mL, 1.87 mmol) and diisopropyl azodicarboxylate
(0.39 g, 2 mmol). The mixture was stirred for 18 hours at
23.degree. C. The mixture was concentrated and purified via Isco
chromatography (Redisep, silica, gradient 0-50% ethyl acetate in
hexane) to afford 0.44 g of
1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide.
[0302] HPLC purity 99.1% at 210-370 nm, 8.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for
[0303] 10 minutes hold 4 minutes
[0304] Step 2:
1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.44 g, 1.64 mmol) was dissolved in CH.sub.2Cl.sub.2
(10 mL) at 23.degree. C. 3-chlorobenzoperoxoic acid (1.02 g, 3.9
mmol) was added and the mixture allowed to stir for 18 h then
filtered and concentrated. The residue was diluted with EtOAc and
washed with 10% NaHCO.sub.3 solution then brine. After drying with
Na.sub.2SO.sub.4 the solution was concentrated then 300 mg of the
residue was dissolved in 10 mL of MeNH.sub.2 solution (8M in EtOH).
The solution was irradiated in a microwave cuvette at 100.degree.
C. for 3 minutes. The reaction mixture was concentrated then loaded
directly onto silica gel and purified via Isco chromatography
(Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in
dichloromethane) to afford 300 mg of racemic
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol.
[0305] HRMS: calculated for C17H15FN2O+H+, 366.1288; found (ESI,
[M+H]+), 366.1279
[0306] HPLC purity 100% at 210-370 nm, 6.9 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0307] Step 3: Approximately 300 mg of racemic
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol was dissolved in 4 mL of methanol. 200 .mu.L of
the resulting solution was repetitively injected onto the
Supercritical Fluid Chromatography instrument, and the baseline
resolved enantiomers were separately collected using the conditions
described below. The chiral purity of each enantiomer was
determined under the same Supercritical Fluid Chromatography
conditions using a 250 mm.times.4.6 mm ID column at 2.0 mL/min flow
rate using Chiralpak AS-H 5 Analytical Supercritical Fluid
Chromatography (Berger Instruments, Inc. Newark, Del.). Both
enantiomers were found to be >99.9% enantiomerically pure.
[0308] SFC Instrument: Berger MultiGram Prep SFC (Berger
Instruments, Inc. Newark, Del.) [0309] Column: Chiralpak AS-H; 5
.mu.m; 250 mm L.times.20 mm ID (Chiral Technologies, Inc, Exton,
Pa.) [0310] Column temperature: 35.degree. C. [0311] SFC Modifier:
18% MeOHw 0.2% DMEA [0312] Flow rate: 50 mL/min [0313] Outlet
Pressure: 100 bar [0314] Detector: UV at 220 nm.
Example 3A
(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(m-
ethylamino)butan-2-ol
##STR00032## ##STR00033##
[0316] Step 1: To a solution of
N1-(2-fluorophenyl)benzene-1,2-diamine, 1, (1 g, 5 mmol) in
methanol (100 mL) was added the aldehyde (0.72 g, 5 mmol) followed
by acetic acid (0.12 mL, 2 mmol) and sodium cyanoborohydride (3.15
g, 50 mmol). The reaction was stirred for 8 hour at 23.degree. C.
then NaHCO.sub.3 solution (50 mL) added. The mixture was extracted
with EtOAC (3.times.) and the combined organic layers washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was
purified via HPLC (SFC, 10% MeOH in CO.sub.2, 20.times.250 mm
Kromasil CN) to afford 0.74 g (68%) of the desired product 2 as a
clear oil.
[0317] HPLC purity 99.4% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[0318] Step 2: To a solution of 2 (0.53 g, 1.6 mmol) in THF (20 mL)
at 0.degree. C. was added triethylamine (0.68 mL, 4.8 mmol)
followed by thionyl chloride (0.17 ml, 2.4 mmol) dropwise. The
reaction was allowed to stir for 0.5 h then diluted with EtOAc and
washed with water and brine. After drying with Na.sub.2SO.sub.4 the
solution was concentrated then purified via Isco chromatography
(Redisep, silica, gradient 0-50% EtOAc) to afford 0.56 g (93%) of 3
as a clear oil.
[0319] HRMS: calcd for C19H21FN2O3S+H+, 377.1330; found (ESI,
[M+H]+), 377.1331
[0320] HPLC purity 53.4% (unstable) at 210-370 nm, 3.7 min.; Xterra
RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[0321] Step 3: 3 (0.46 g, 1.22 mmol) was dissolved in
acetonitrile/water (1:1, 20 mL) at 0.degree. C. Sodium Periodate
(0.39 g, 1.8 mmol) was added followed by
RuCl.sub.3.(H.sub.2O).sub.x (11 mg, catalytic) and the mixture was
stirred for 1 h then filtered through Celite. The mixture was
diluted with EtOAc, washed with water and brine then dried with
Na.sub.2SO.sub.4 and concentrated. The residue was purified via
Isco chromatography (Redisep, silica, gradient 0-50% EtOAc) to
afford 0.45 g (94%) of 4 as a clear oil.
[0322] HRMS: calcd for C19H21FN2O4S+H+, 393.128; found (ESI,
[M+H]+), 393.1279
[0323] HPLC purity 100% at 210-370 nm, 10 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[0324] Step 4: 4 (0.425 g, 1.1 mmol) was dissolved in THF (20 mL)
at 23.degree. C. 2N HCl (10 mL) was added dropwise and the mixture
was stirred for 4 h then a saturated solution of NaHCO.sub.3 added
slowly. The mixture was extracted with CH.sub.2Cl.sub.2 (4.times.)
and the combined layers washed with brine, dried with
Na.sub.2SO.sub.4 and concentrated. The residue was purified via
Isco chromatography (Redisep, silica, gradient 0-100% EtOAc) to
afford 0.325 g (85%) of 5 as a clear oil.
[0325] HRMS: calcd for C16H17FN2O4S+H+, 353.0966; found (ESI,
[M+H]+), 353.0969.
[0326] HPLC purity 100% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[0327] Step 5: 5 (0.29 g, 0.82 mmol) was dissolved in
CH.sub.2Cl.sub.2 (15 mL) at 0.degree. C. Triethylamine (0.14 mL,
0.99 mmol) was added followed by p-toluenesulfonyl chloride (0.17
g, 0.9 mmol). The mixture was stirred at 0.degree. C. for 1 hour
then allowed to warm to 23.degree. C. over 6 h. The reaction was
washed with water, a 10% HCl solution, NaHCO.sub.3 and brine. After
drying with Na.sub.2SO.sub.4 and concentration, the residue was
purified via Isco chromatography (Redisep, silica, gradient 0-60%
EtOAc) to afford 0.229 g (55%) of 6 as a clear oil.
[0328] HRMS: calcd for C23H23FN2O6S2+H+, 507.1054; found (ESI,
[M+H]+), 507.1056.
[0329] HPLC purity 98.5% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[0330] Step 6: 6 (0.2 g, 0.4 mmol) was dissolved in MeOH/THF (1:1,
10 mL) at 23.degree. C. Potassium carbonate (0.06 g, 0.43 mmol) was
added and the reaction was stirred at 23.degree. C. for 18 hour
then diluted with CH.sub.2Cl.sub.2 (20 mL). The reaction was washed
with water, dried over Na.sub.2SO.sub.4, concentrated and purified
via Isco chromatography (Redisep, silica, gradient 0-50% EtOAc) to
afford 0.08 g (60%) of 7 as a clear oil.
[0331] HRMS: calcd for C16H15FN2O3S+H+, 335.086; found (ESI,
[M+H]+), 335.0863.
[0332] HPLC purity 98.4% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[0333] Step 7: 7 (0.08 g, 0.23 mmol) was dissolved in MeNH.sub.2
solution (8M in EtOH, 10 mL). The solution was heated to 60.degree.
C. for 1 hour. The reaction mixture was cooled and concentrated
then loaded directly onto silica gel and purified via Isco
chromatography (Redisep, silica, gradient 0-100% of 10% 7M ammonia
in MeOH/dichloromethane) to afford 0.08 g (95%) of 8 as a foamy
oil. This was dissolved in CH.sub.2Cl.sub.2 (5 mL) and HCl added
(4N in dioxane, 0.11 mL). After stirring for 30 minutes at
23.degree. C. the mixture was concentrated then redissolved in
CH.sub.2Cl.sub.2 (2 mL) and tert-butyl methyl ether added until the
solution was almost cloudy. The solution was allowed to sit for
several hours at 23.degree. C. until crystals had formed. These
were collected by filtration and dried under vacuo.
[0334] HRMS: calcd for C16H15FN2O3S+H+, 366.1282; found (ESI,
[M+H]+), 366.1287.
[0335] HPLC purity 100% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 3B
Alternative Asymmetric route to
(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)butan-2-ol
##STR00034##
[0337] Step 1:
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.5 g, 1.9 mmol) was dissolved in acetone (5 mL) and potassium
carbonate (0.52 g, 3.8 mmol) was added followed by
S(-)-4-bromo-1,2-epoxybutane (0.57 g, 3.8 mmol). The mixture was
stirred for 18 hours at 50.degree. C. in a sealed vial then diluted
with EtOAc (100 mL) and washed with water (2.times.), brine then
dried (Na.sub.2SO.sub.4). After concentration the residue was
dissolved in 10 mL of MeNH.sub.2 solution (8M in EtOH). The
solution was irradiated in a microwave cuvette at 10.degree. C. for
3 minutes. The reaction mixture was concentrated then loaded
directly onto silica gel and purified via Isco chromatography
(Redisep, silica, gradient 0-100% of 10% 7M ammonia in
MeOH/dichloromethane) to afford 387 mg of
(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)butan-2-ol.
[0338] HRMS: calcd for C17H20FN3O3S+H+, 366.1288; found (ESI,
[M+H]+), 366.1279
[0339] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 4
1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]b-
utan-2-ol
##STR00035##
[0341] Step 1:
1-(but-3-enyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.44 g, 1.64 mmol) was dissolved in CH.sub.2Cl.sub.2
(10 mL) at 23.degree. C. 3-chlorobenzoperoxoic acid (1.02 g, 3.9
mmol) was added and the mixture allowed to stir for 18 h then
filtered and concentrated. The residue was diluted with EtOAc and
washed with 10% NaHCO.sub.3 solution then brine. After drying with
Na.sub.2SO.sub.4 the solution was concentrated then 50 mg of the
residue was dissolved in 2 mL of NH.sub.3 solution (7M in MeOH).
The solution was irradiated in a microwave cuvette at 100.degree.
C. for 3 minutes. The reaction mixture was concentrated then loaded
directly onto silica gel and purified via Isco chromatography
(Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in
dichloromethane) to afford 20 mg of
1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
butan-2-ol.
[0342] HRMS: calculated for C17H15FN2O+H+, 352.1131; found (ESI,
[M+H]+), 352.1129
[0343] HPLC purity 89.4% at 210-370 nm, 6.8 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes
Example 5
3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benz-
othiadiazol-1(3H)-yl}phenol hydrochloride
##STR00036##
[0345] Step 1: In an analogous manner to example 3B,
(2S)-4-[3-(2-fluoro,
4-((2-(trimethylsilyl)ethoxy)methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]-1-(methylamino)butan-2-ol was prepared from
1-(4-bromobutyl)-3-(2-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-
-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
S(-)-4-bromo-1,2-epoxybutane and methylamine (33% in ethanol).
[0346] Step 3: The product from Step 1 was dissolved in 9:1
ether:methanol and 2N HCl in ether added. After allowing to stand
overnight a solid formed which was remover by filtration to afford
3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl}phenol hydrochloride.
[0347] MS (ES) m/z 382.1; HPLC purity 95.5% at 210-370 nm, 6.4
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85115-5195 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4
min. HRMS: calcd for C17H20FN3O4S+H+, 382.12313; found (ESI, [M+H]+
Obs'd), 382.1233.
Example 6
5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methy-
lamino)pentan-2-ol
##STR00037##
[0349] Example 6 was prepared using
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 4-penten-1-ol analogous to the conditions used in example
1.
[0350] HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI,
[M+H]+), 380.1439
[0351] HPLC purity 97.5% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 7
(2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]butan-2-ol
##STR00038##
[0353] Example 7 was prepared using
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide and ammonia analogous to the conditions used
in step 2 of example 1.
[0354] HRMS: calcd for C16H18FN3O3S+H+, 352.1126; found (ESI,
[M+H]+), 352.1126
[0355] HPLC purity 78.8% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 8
(2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)pentan-2-ol
##STR00039##
[0357] Example 8 was prepared using
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 4-penten-1-ol analogous to the conditions used in example
1.
[0358] HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI,
[M+H]+), 380.1444
[0359] HPLC purity 91.1% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 9
(2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)pentan-2-ol
##STR00040##
[0361] Example 9 was prepared using
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 4-penten-1-ol analogous to the conditions used in example 1
[0362] HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI,
[M+H]+), 380.1446
[0363] HPLC purity 94.7% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 10
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)buta-
n-2-ol
##STR00041##
[0365] Example 10 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and ethylamine analogous to the conditions used in step
2 of example 1.
[0366] HRMS: calcd for C18H23N3O3S+H+,
[0367] HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 11
1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)b-
utan-2-ol
##STR00042##
[0369] Example 11 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and dimethylamine analogous to the conditions used in
step 2 of example 1.
[0370] HRMS: calcd for C.sub.18H.sub.23N.sub.3O.sub.3S+H+,
362.1533; found (ESI, [M+H]+), 362.1536
[0371] HPLC purity 99.3% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 12
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)-
butan-2-ol
##STR00043##
[0373] Example 12 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and isopropylamine analogous to the conditions used in
step 2 of example 1.
[0374] HRMS: calcd for C19H25N3O3S+H+, 376.1689; found (ESI,
[M+H]+), 376.1695
[0375] HPLC purity 97.3% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 13
1-(cycloprolylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-ol
##STR00044##
[0377] Example 13 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and cyclopropylamine analogous to the conditions used
in step 2 of example 1.
[0378] HRMS: calcd for C19H23N3O3S+H+, 374.1533; found (ESI,
[M+H]+), 374.1537
[0379] HPLC purity 100% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 14
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)butan-2-ol
##STR00045##
[0381] Example 14 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and t-butylamine analogous to the conditions used in
step 2 of example 1.
[0382] HRMS: calcd for C20H27N3O.sub.3S+H+, 390.1846; found (ESI,
[M+H]+), 390.1850
[0383] HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 15
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)but-
an-2-ol
##STR00046##
[0385] Example 15 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and methylamine analogous to the conditions used in
step 2 of example 1.
[0386] HRMS: calcd for C17H21N3O3S+H+, 348.1376; found (ESI,
[M+H]+), 348.1381
[0387] HPLC purity 99.7% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 16
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamin-
o)butan-2-ol
##STR00047##
[0389] Example 16 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and methylamine analogous to the conditions used in
step 2 of example 1.
[0390] HRMS: calcd for C17H21N3O3S+H+, 348.1376; found (ESI,
[M+H]+), 348.1381
[0391] HPLC purity 97.5% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 17
(2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-
-yl)butan-2-ol
##STR00048##
[0393] Example 17 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and methylamine analogous to the conditions used in
step 2 of example 1.
[0394] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+), 362.1537
[0395] HPLC purity 100% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 18
(2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-
-yl)butan-2-ol
##STR00049##
[0397] Example 18 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and dimethylamine analogous to the conditions used in
step 2 of example 1.
[0398] HRMS: calcd for C.sub.18H.sub.23N.sub.3O.sub.3S+H+,
362.1533; found (ESI, [M+H]+), 362.1537
[0399] HPLC purity 100% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 19
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropyla-
mino)butan-2-ol
##STR00050##
[0401] Example 19 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and isopropylamine analogous to the conditions used in
step 2 of example 1.
[0402] HRMS: calcd for C19H25N3O3S+H+, 376.1689; found (ESI,
[M+H]+), 376.1697
[0403] HPLC purity 100% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 20
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropyla-
mino)butan-2-ol
##STR00051##
[0405] Example 20 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and isopropylamine analogous to the conditions used in
step 2 of example 1.
[0406] HRMS: calcd for C19H25N3O3S+H+, 376.1689; found (ESI,
[M+H]+), 376.1697
[0407] HPLC purity 98.7% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 21
(2S)-1-(cycloprolylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(-
3H)-yl)butan-2-ol
##STR00052##
[0409] Example 21 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and cyclopropylamine analogous to the conditions used
in step 2 of example 1.
[0410] HRMS: calcd for C19H23N3O3S+H+, 374.1533; found (ESI,
[M+H]+), 374.1536
[0411] HPLC purity 98.0% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 22
(2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3-
H)-yl)butan-2-ol
##STR00053##
[0413] Example 22 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and t-butylamine analogous to the conditions used in
step 2 of example 1.
[0414] HRMS: calcd for C20H27N3O3S+H+, 390.1846; found (ESI,
[M+H]+), 390.1854
[0415] HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 23
(2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3-
H)-yl)butan-2-ol
##STR00054##
[0417] Example 23 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and t-butylamine analogous to the conditions used in
step 2 of example 1.
[0418] HRMS: calcd for C20H27N3O3S+H+, 390.1846; found (ESI,
[M+H]+), 390.1853
[0419] HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 24
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino-
)butan-2-ol
##STR00055##
[0421] Example 24 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and ethylamine analogous to the conditions used in step
2 of example 1.
[0422] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+), 362.1540
[0423] HPLC purity 99.4% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 25
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino-
)butan-2-ol
##STR00056##
[0425] Example 25 was prepared using
1-(2-oxiran-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and ethylamine analogous to the conditions used in step
2 of example 1.
[0426] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+), 362.1539
[0427] HPLC purity 99.3% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 26
(2S)-1-(cycloprolylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol
##STR00057##
[0429] Example 26 was prepared using
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide and cyclopropylamine analogous to the
conditions used in step 2 of example 1.
[0430] HRMS: calcd for C19H22FN3O3S+H+, 392.1439; found (ESI,
[M+H]+), 392.1441
[0431] HPLC purity 95.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 27
(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol
##STR00058##
[0433] Example 27 was prepared using
1-(2-methylphenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide and cyclopropylamine analogous to the
conditions used in step 2 of example 1.
[0434] HRMS: calcd for C20H25N3O3S+H+, 388.1689; found (ESI,
[M+H]+), 388.1690
[0435] HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 28
(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benz-
othiadiazol-1(3H)-yl]butan-2-ol
##STR00059##
[0437] Example 28 was prepared using
1-(2,4-difluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the
conditions used in step 2 of example 1.
[0438] HRMS: calcd for C19H21F2N3O3S+H+, 410.1345; found (ESI,
[M+H]+), 410.1344
[0439] HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 29
(2S)-1-(cycloprolylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benz-
othiadiazol-1(3H)-yl]butan-2-ol
##STR00060##
[0441] Example 29 was prepared using
1-(2,5-difluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the
conditions used in step 2 of example 1.
[0442] HRMS: calcd for C19H21F2N3O3S+H+, 410.1345; found (ESI,
[M+H]+), 410.1347
[0443] HPLC purity 96.0% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 30
(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benz-
othiadiazol-1(3H)-yl]butan-2-ol
##STR00061##
[0445] Example 30 was prepared using
1-(2,6-difluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide and cyclopropylamine analogous to the
conditions used in step 2 of example 1.
[0446] HRMS: calcd for C19H21F2N3O3S+H+, 410.1345; found (ESI,
[M+H]+), 410.1345
[0447] HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 31
(2S)-1-(cycloprolylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol
##STR00062##
[0449] Example 31 was prepared using
1-(3-methoxyphenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide and cyclopropylamine analogous to the
conditions used in step 2 of example 1.
[0450] HRMS: calcd for C20H25N3O4S+H+, 404.1639; found (ESI,
[M+H]+), 404.1641
[0451] HPLC purity 98.1% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 32
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamin-
o)butan-2-ol
##STR00063##
[0453] This compound was prepared using
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
S(-)-4-bromo-1,2-epoxybutane and methylamine analogous to the
conditions used in example 3B.
[0454] HRMS: HRMS: calcd for C17H21N3O3S+H+, 348.1376; found (ESI,
[M+H]+), 348.1384.
[0455] HPLC purity 97.8% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 33
(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-1-(methylamino)butan-2-ol
##STR00064##
[0457] This compound was prepared using
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, S(-)-4-bromo-1,2-epoxybutane and methylamine analogous
to the conditions used in example 3B.
[0458] HRMS: HRMS: calcd for C17H19F2N3O3S+H+, 384.1194; found
(ESI, [M+H]+), 384.1188.
[0459] HPLC purity 95.9% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 34
(2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-1-(methylamino)butan-2-ol
##STR00065##
[0461] This compound was prepared using
1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, S(-)-4-bromo-1,2-epoxybutane and methylamine analogous
to the conditions used in example 3B.
[0462] HRMS: HRMS: calcd for C17H19F2N3O3S+H+, 384.1192; found
(ESI, [M+H]+), 384.1188.
[0463] HPLC purity 80.3% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 35
(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-1-(methylamino)butan-2-ol
##STR00066##
[0465] This compound was prepared using
1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, S(-)-4-bromo-1,2-epoxybutane and methylamine analogous
to the conditions used in example 3B.
[0466] HRMS: C17H19F2N3O3S+H+, (ESI, [M+H]+), 378.1485
[0467] HPLC purity 100% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 36
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-1-(methylamino)butan-2-ol
##STR00067##
[0469] This compound was prepared using
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, S(-)-4-bromo-1,2-epoxybutane and methylamine analogous
to the conditions used in example 3B.
[0470] HRMS: calcd for C17H19F2N3O3S+H+, 353.0766; found (ESI,
[M+H]+, 353.0768.
[0471] HPLC purity 98.0% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 37
(2S)-4-[3-(4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol
##STR00068##
[0473] This compound was prepared using
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
S(-)-4-bromo-1,2-epoxybutane and methylamine analogous to the
conditions used in example 3B.
[0474] HRMS: calcd for C17H19FN3O3S+H+, 366.1282; found (ESI,
[M+H]+, 366.1287.
[0475] HPLC purity 84.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 38
(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiaz-
ol-1(3H)-yl]butan-2-ol
##STR00069##
[0477] This compound was prepared using
1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
S(-)-4-bromo-1,2-epoxybutane and methylamine analogous to the
conditions used in example 3B.
[0478] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+, 362.1538
[0479] HPLC purity 78.6% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 39
(2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)butan-2-ol
##STR00070##
[0481] This compound was prepared using
1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
S(-)-4-bromo-1,2-epoxybutane and methylamine analogous to the
conditions used in example 3B.
[0482] HRMS: calcd for C17H20ClN.sub.3O3S+H+, 382.0987; found (ESI,
[M+H]+, 382.0993
[0483] HPLC purity 77.4% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 40
(S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)butan-2-ol
##STR00071##
[0485] This compound was prepared using
1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
S(-)-4-bromo-1,2-epoxybutane and methylamine analogous to the
conditions used in example 3B.
[0486] HRMS: calcd for C18H23N3O23S+H+, 378.1482; found (ESI,
[M+H]+), 378.1484
[0487] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 41
(R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
1-(methylamino)butan-2-ol
##STR00072##
[0489] Step 1:
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.15 g, 0.5 mmol) was dissolved in acetone (5 mL) and
potassium carbonate (0.14 g, 1.0 mmol) was added followed by
(R)-2-(oxiran-2-yl)ethyl 4-tosylate (0.24 g, 1.0 mmol). The mixture
was stirred for 18 hours at 50.degree. C. in a sealed vial then
diluted with EtOAc (100 mL) and washed with water (2.times.), brine
then dried (Na.sub.2SO.sub.4). After concentration the residue was
dissolved in 10 mL of MeNH.sub.2 solution (8M in EtOH). The
solution was irradiated in a microwave cuvette at 100.degree. C.
for 3 minutes. The reaction mixture was concentrated then loaded
directly onto silica gel and purified via Isco chromatography
(Redisep, silica, gradient 0-100% of 10% 7M ammonia in
MeOH/dichloromethane) to afford 59 mg of
(R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-1-(methylamino)butan-2-ol.
[0490] HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI,
[M+H]+), 384.1191
[0491] HPLC purity 79.9% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 42
(R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
1-(methylamino)butan-2-ol
##STR00073##
[0493] This compound was prepared using
1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine
analogous to the conditions used in example 41.
[0494] HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI,
[M+H]+), 384.1190
[0495] HPLC purity 93.6% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 43
(R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
1-(methylamino)butan-2-ol
##STR00074##
[0497] This compound was prepared using
1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine
analogous to the conditions used in example 41.
[0498] HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI,
[M+H]+), 384.1189
[0499] HPLC purity 92.8% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 44
(R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
1-(methylamino)butan-2-ol
##STR00075##
[0501] This compound was prepared using
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, (R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine
analogous to the conditions used in example 41.
[0502] HRMS: calcd for C17H19F2N3O3S+H+, 384.1188; found (ESI,
[M+H]+), 384.1193
[0503] HPLC purity 86.6% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 45
(R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(m-
ethylamino)butan-2-ol
##STR00076##
[0505] This compound was prepared using
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to
the conditions used in example 41.
[0506] HRMS: calcd for C17H20FN3O3S+H+, 366.1282; found (ESI,
[M+H]+), 366.1291
[0507] HPLC purity 94.2% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 46
(2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiaz-
ol-1(3H)-yl]butan-2-ol
##STR00077##
[0509] This compound was prepared using
1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to
the conditions used in example 41.
[0510] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+), 362.1538
[0511] HPLC purity 94.5% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85115-5195 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 47
(R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(m-
ethylamino)butan-2-ol
##STR00078##
[0513] This compound was prepared using
1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to
the conditions used in example 41.
[0514] HRMS: calcd for C17H20ClN3O3S+H+, 382.0987; found (ESI,
[M+H]+), 382.099
[0515] HPLC purity 94.1% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 48
(R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)butan-2-ol
##STR00079##
[0517] This compound was prepared using
1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide,
(R)-2-(oxiran-2-yl)ethyl 4-tosylate and methylamine analogous to
the conditions used in example 41.
[0518] HRMS: calcd for C18H23N3O23S+H+, 378.1482; found (ESI,
[M+H]+), 378.149
[0519] HPLC purity 95.3% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 49
(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]butan-2-ol hydrochloride
##STR00080##
[0521] Step 1: In an analogous manner to Example 3B,
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with
cyclobutylamine (1 mL, 12 mmol) in methanol to give
(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric
acid in ether to give its hydrochloride salt as a white solid (0.59
g, 44%). HRMS: calcd for C.sub.20H.sub.24FN.sub.3O.sub.3S+H.sup.+,
406.15952; found (ESI, [M+H].sup.+ Obs'd), 406.1591. HPLC retention
time: 7.5 min.
Example 50
(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol hydrochloride
##STR00081##
[0523] Step 1: In an analogous manner to Example 3B,
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with
cyclopentylamine (1.2 mL, 12 mmol) in methanol to give
(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric
acid in ether to give its hydrochloride salt as a white solid (0.67
g, 49%). HRMS: calcd for C.sub.21H.sub.26FN.sub.3O.sub.3S+H.sup.+,
420.17517; found (ESI, [M+H].sup.+ Obs'd), 420.1746. HPLC retention
time: 7.8 min.
Example 51
(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]butan-2-ol hydrochloride
##STR00082##
[0525] Step 1: In an analogous manner to Example 3B,
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with
cyclohexylamine (1.4 mL, 12 mmol) in methanol to give
(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric
acid in ether to give hydrochloride salt as a white solid (0.84 g,
59%). HRMS: calcd for C.sub.22H.sub.28FN.sub.3O.sub.3S+H.sup.+,
434.19082; found (ESI, [M+H].sup.+ Obs'd), 434.1902. HPLC retention
time: 8.1 min.
Example 52
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
isopropylamino)butan-2-ol hydrochloride
##STR00083##
[0527] Step 1: In an analogous manner to Example 3B,
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with
cyclohexylamine (1.4 mL, 12 mmol) in methanol to give
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(isopropylamino)butan-2-ol which was treated with 1N hydrochloric
acid in ether to give its hydrochloride salt as a white solid (0.74
g, 57%). HRMS: calcd for C.sub.19H.sub.24FN.sub.3O.sub.3S+H.sup.+,
394.15952; found (ESI, [M+H].sup.+ Obs'd), 394.1590. HPLC retention
time: 7.3 min.
Example 53
(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazo-
l-1(3H)-yl]butan-2-ol hydrochloride
##STR00084##
[0529] Step 1: In an analogous manner to Example 3B,
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.1 g, 0.3 mmol) was treated with 30-40%
ethylamine in methanol to give
(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiaz-
ol-1(3H)-yl]butan-2-ol which was treated with 1N hydrochloric acid
in ether to give a white hydrochloride salt (0.74 g, 59%). MS (ES)
m/z 379.9 ([M+H].sup.+). HPLC retention time: 7.0 min.
[0530] hNET Assay Procedure Protocol A: Inhibition of [.sup.3H] NE
Uptake into Cloned Human NE Transporters (MDCK Cells) ("hNET
Uptake")
[0531] The hNET uptake assay procedure was used to screen for
compounds that inhibit the reuptake of norepinephrine and to
determine IC.sub.50 values for compounds identified as hNET
reuptake inhibitors.
Materials and Methods:
Cell Line and Culture Reagents:
[0532] [.sup.3H] NE uptake studies were performed using MDCK cells
stably expressing human norepinephrine transporter (hNET) (See
Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning
of a cocaine- and antidepressant-sensitive human noradrenaline
transporter. Nature. 350:350-354) cultured in growth medium
containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS
(dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129HI)
and 500 .mu.g/ml G418 (Gibco, Cat. No. 10131). Cells were seeded at
300,000/T75 flask, and split twice weekly.
Norepinephrine Uptake Assays:
[0533] All uptake experiments were performed in 96-well plates
(Falcon Optilux, cat #353947) in a total volume of 250 .mu.l/well.
MDCK cells were plated at 50,000 cells/well. At the time of the
assay, the media was removed, and 200 .mu.l assay buffer (25 mM
Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl.sub.2, 1.2 mM
MgSO.sub.4.7H.sub.2O, 2 mg/ml glucose, 0.2 mg/ml ascorbic acid, 1
.mu.M pargyline, pH 7.4) was added to each well. 25 .mu.l of each
test compound was subsequently added to plates in triplicate and
incubated at 37.degree. C. for 5 minutes. All test compounds were
dissolved in 100% DMSO and diluted in 4% DMSO/H.sub.2O, and assayed
using a 7-point dose response curve (1 nM-10 .mu.M). Next, 25 .mu.l
of [.sup.3H] NE (74.9 Ci/mmol, Perkin Elmer, Boston, Mass.) was
added to all wells and incubated at 37.degree. C. for an additional
5 minutes. Non-specific uptake was defined by 20 .mu.M desipramine.
The final concentrations of [.sup.3H] NE was 16 nM, respectively.
The reaction was terminated by aspiration and washed with ice cold
50 mM Tris (pH 7.4). The plates were left to air dry for roughly 30
min, and MDCK cells were lysed by the addition of 25 .mu.l of 0.25
M NaOH. 100 .mu.l of Microscint-20 were added to each well
(Packard, Perkin Elmer, Boston, Mass.), and the plates were counted
using a TopCount (Perkin Elmer, Downer's Grove, Ill.) liquid
scintillation counter.
[0534] Analysis of Results:
[0535] % Inhibition of uptake=((mean cpm control wells-each cpm
drug well)/(mean cpm control wells-non-specific
wells).times.100.
[0536] IC.sub.50 values were calculated using a Prism.RTM.
nonlinear regression program where % inhibition is plotted versus
concentration of inhibitor.
[0537] See: Pacholczyk T, Blakely R D and Amara S G (1991)
Expression cloning of a cocaine- and antidepressant-sensitive human
noradrenaline transporter. Nature. 350:350-354.
[0538] See also: Ramamoorthy J D, Ramamoorthy S, Papapetropoulos A,
Catravas J D, Leibach F H and Ganaphthy V (1995) Cyclic
AMP-independent up-regulation of the human serotonin transporter by
staurosporine in choriocarcinoma cells. Journal of Biological
Chemistry. 270:17189-17195, the contents of which is hereby
incorporated by reference.
[0539] hNET Assay Procedure Protocol B: Cell Based Norepinephrine
(NE) Reuptake Assay Using the Recombinant Human Norepinephrine
Transporter (hNET) ("hNET Uptake")
[0540] The hNET uptake assay procedure was used to screen for
compounds that inhibit the reuptake of norepinephrine and to
determine IC.sub.50 values for compounds identified as hNET
reuptake inhibitors.
Materials and Methods:
Compounds:
[0541] For screening, hydrochloride salts of compounds were
dissolved in solution and 25 .mu.l aliquots of compound solution at
a 1 .mu.M or 10 .mu.M final concentration delivered directly to
cells. For IC.sub.50 determinations, stock compounds were prepared
at 10 mM from powder. The stock solution was diluted according to
compound testing range. Typically, the compound testing range was
from 6 nM to 6 .mu.M by half log dilutions. On the day of assay, 25
.mu.l of compound solution at the specified concentrations was
added to the plates containing cells. A DMSO stock of desipramine
was prepared at 10 mM in DMSO and diluted for a final concentration
of 20 .mu.M to determine the non-specific reuptake. The radioligand
in this assay is .sup.3H-norepinephrine (NE) (PerkinElmer; NET678;
40-80 Ci/mmol) was delivered at approximately 16 nM final
concentration for both single point testing and compound IC.sub.50
determinations.
Tissue Culture Conditions:
[0542] MDCK-Net6 cells, stably transfected with human hNET (See
Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning
of a cocaine- and antidepressant-sensitive human noradrenaline
transporter. Nature. 350:350-354) was maintained in growth media
[high glucose DMEM (Gibco Cat. 11995), 10% FBS (dialyzed,
heat-inactivated, Sigma, dialysed, heat inactivated, Lot#
K.sub.0922 or equivalent) 1.times.Pen/Strep, and 500 .mu.g/ml G418
(Gibco Cat. 10131)]. Cells were plated at 300,000/T75 flask and
cells were split twice weekly.
Functional Reuptake Assay:
[0543] Cells were plated at 3,000 cells/well on day 1 in BD Falcon
Microtest 96-well sterile cell culture plates, Optilux White/Clear
Bottom TC plate (VWR; # 62406-466 or equivalent) in growth media
and maintained in a cell incubator (37.degree. C., 5% CO.sub.2). On
Day 2, cells were removed from the cell incubator and the growth
media is replaced by 200 .mu.l of assay buffer (25 mm HEPES 120 mM
NaCL; 5 mM KCl; 2.5 mM CaCl.sub.2; 1.2 mM MgSO.sub.4; 2 mg/ml
glucose (pH 7.4, 37.degree. C.)) containing 0.2 mg/ml ascorbic acid
and 1 .mu.M parglyine. For screening, 25 .mu.l of compound in 4%
DMSO is added directly to each well and the plate is incubated for
5 min (37.degree. C.). To initiate the norepinephrine reuptake, 16
nM (final concentration) of .sup.3H norepinephrine (specific
activity; 40-80 Ci/mmol) in assay buffer was delivered in 25 .mu.l
aliquots to each well, and the plates were incubated for 5 min at
37.degree. C. The reaction was aspirated from the plate and the
cells washed with 250 .mu.l of 50 mM Tris Buffer (4.degree. C.).
The plates were left to dry for 1 hour. The cells were lysed using
0.25 M NaOH solution then placed on a shake table and vigorously
shaken for 10 min. After cell lysis, 100 .mu.l of Microscint 20
(PerkinElmer; #87-051101) was added to the plates and the plates
were sealed with film tape and replaced on the shake table for a
minimum of 10 min. The plates were counted in a TopCount counter
(PerkinElmer).
Analysis of Results:
[0544] For screening single point determinations, each compound
plate contained at least 3 control wells (maximum NE reuptake
determinant) and 3 non-specific wells determined by adding 20 .mu.M
of desipramine (minimum NE reuptake determinant). Determination of
active compounds were calculated using a Microsoft Excel spread
sheet applying the following formula:
% inhibition=[1-((mean cpm test compound wells-mean cpm
non-specific wells)/(mean cpm control wells-mean cpm non-specific
wells))].times.100
[0545] For IC.sub.50 determination, raw cpm values were generated
in a data file from the TopCount counter. The data was organized
Microsoft Excel and transferred into PRIZM graphing and statistical
program, which calculated the estimated IC.sub.50 value.
Calculation of IC.sub.50 values was made using non-linear
regression analysis with a sigmoidal dose response with variable
slope. The statistical program used wells containing .sup.3H
norepinephrine only as the maximal NE reuptake determinant and
wells containing .sup.3H norepinephrine plus 20 .mu.M desipramine
as the minimal NE reuptake determinant (non-specific determinant).
Estimation of the IC.sub.50 value is completed on a log scale and
the line is fit between the maximal and minimal NE reuptake values.
In the event that the highest test concentration does not exceed
50% reuptake inhibition, data will be reported as percent maximal
NE reuptake at the highest concentration tested.
[0546] See: Pacholczyk, T., Blakely, R. D., and Amara, S. G. (1991)
Expression cloning of a cocaine- and antidepressant-sensitive human
noradrenaline transporter. Nature, 350, 350-354, the contents of
which is hereby incorporated by reference.
[0547] Results are shown in the following table:
TABLE-US-00001 NE uptake (Protocol B) Example IC.sub.50 (nM) 1 7.3
2 2.68 3 1.35 3A 3B 4 8.73 5 4 6 186 7 32 8 109 9 465 10 196 11 481
12 2255 13 9 14 853 15 2 16 3 17 252 18 278 19 2294 20 1158 21 6 22
3243 23 765 24 148 25 193 26 13 27 358 28 214 29 34 30 13 31 292 32
4 33 4 34 43 35 3 36 18 37 146 38 64 39 28 40 25 41 9 42 394 43 10
44 100 45 328 46 294 47 61 48 143 49 415 50 3833 51 5019 52 2118 53
104
Rat Liver Microsomal Stability Assay:
[0548] DMSO stock solutions of test compounds were prepared at 0.5
mM concentration. Diluted solutions of test compounds were prepared
by adding 50 uL of each DMSO stock solution to 200 uL of
acetonitrile to make 0.1 mM solutions in 20% DMSO/80% acetonitrile.
Rat liver microsomal solution was prepared by adding 1.582 mL of
concentrated rat liver microsomes (20 mg/mL protein concentration)
to 48.291 mL of pre-warmed (to 37.degree. C.) 0.1M potassium
phosphate buffer (pH 7.4) containing 127 uL of 0.5 M EDTA to make a
0.6329 mg/mL (protein) microsomal solution. 11.2 uL of each test
compound diluted solution was each added directly to 885 uL of rat
liver microsomal solution (allowing direct binding of drugs to
microsomal proteins and lipids to minimize precipitation and
non-specific binding to the plasticware). This solution was mixed
and 180 uL was transferred to "Time 0" and "Time 15 min" plates
(each in duplicate wells). For the Time 15 min plate, NADPH
regenerating agent (45 uL) was added to each well to initiate the
reaction, the plate was incubated at 37.degree. C. for 15 min,
followed by quenching of the reaction by adding 450 uL of cold
acetonitrile to each well. For the Time 0 plate, 450 uL of cold
acetonitrile was added to each well, followed by addition of NADPH
regenerating agent (45 uL) and no incubation. All of the plates
were centrifuged at 3000 rpm for 15 min and the supernatants were
transferred to other well plates for analysis by LC-MS.
Dopamine Transporter (hDAT) Membrane Binding Assay
[0549] The method for this radioligand binding assay was modified
from the methods supplied with hDAT membranes (catalog number
RBHDATM; Perkin Elmer Life Analytical Sciences), and those
modifications are listed within this method section. Frozen
membrane samples from a cell line that expresses hDAT were diluted
to 7.5 ml in binding buffer (50 mM Tris-HCl; pH 7.4, 100 mM NaCl),
homogenized with a tissue-tearer (Polytron PT 120.degree. C.,
Kinematica AG) and delivered at a volume of 75 .mu.l to each well
of a polypropylene 96-well plate. The binding reaction was run in
polypropylene 96-well plates (Costar General Assay Plate, Cat. No.
3359; Lid, Cat. No. 3930). A stock solution of mazindol was
prepared in DMSO (10 mM) and delivered to triplicate wells
containing membrane for a final test concentration of 10 uM.
Mazindol is a DA transporter inhibitor with a 50% inhibitory
concentration (IC.sub.50) value of 18.0.+-.6.0 nM in the present
assays. Data from wells containing mazindol (10 uM) were used to
define non-specific (NSB) hDAT binding (minimum hDAT binding).
Total binding is defined by addition of 5 .mu.l of binding buffer
alone in the presence of [.sup.3H] WIN-35,428. Stock solutions of
compounds to be tested were prepared in DMSO at concentrations of
10 mM to 10 uM. On the day of assay, test compounds were diluted in
assay buffer according to test range (100,000 to 10 nM) ensuring a
maximal DMSO concentration of less than 0.5% in the assay reaction
wells. Homogenized membranes were pre-incubated with test compounds
for 20 min at 4.degree. C. before the initiation of the binding
reaction. The binding reaction is initiated by addition of 25 .mu.l
of .sup.3[H]-WIN 35,428 diluted in binding buffer. The final
concentration of .sup.3[H]-WIN 35,428 delivered was 10 nM. The
K.sub.D value estimated for .sup.3[H]-WIN-35,428 in hDAT membranes
(Lot#296-083-A) was 6.9 nM. The radioligand concentration, [L],
used in the competition binding assays is a factor difference of
1.4 compared to the K.sub.D value and was used to calculate the
K.sub.i value. The plate containing the radioligand binding
reactions were incubated for 2 h at 4.degree. C. on a shaking table
(Bellco, Vineland, N.J.) at 3 revolutions per minute. The
MultiScreen-FB opaque 96-well filtration plates contained Millipore
glass fiber filters (Millipore glass fiber B, Cat. No. MAFBN0B)
were used to terminate the binding reactions and to separate bound
from free radioligand. The plates were presoaked with 0.5%
polyethylenimine (PEI; Sigma Cat. No. P-3143) in water for a
minimum of two hours at room temperature to reduce nonspecific
binding of .sup.3[H]-WIN 35,428 during the harvest procedure.
Before harvesting the reaction plates, the PEI solution is
aspirated from the filter plates using a vacuum manifold. Aliquots
of each reaction (90 .mu.l of each 100 .mu.l reaction well) were
transferred from the reaction plates to the filter plates using a
Zymark Rapid Plate-96 automated pipette station. The binding
reaction is terminated by vacuum filtration through the glass fiber
filters. The filter plates were aspirated at 5-10 inches of Hg, and
the wells are washed 9 times with 200 .mu.l wash buffer (50 mM
Tris-HCl, 0.9% NaCl, pH 7.4; 4.degree. C.) using a 12 channel
aspiration/wash system. Plastic bottom supports are removed from
the filter plates and the plates are placed in plastic liners. A
100 .mu.l aliquot of scintillation fluid was added to each well and
the top of each plate is sealed with adhesive film. The plates are
vigorously shaken at 5 rpm for 10-15 minutes to ensure adequate
equilibration of aqueous to solvent partitioning. The collection of
raw counts per minute (cpm) data was done using a Wallac Microbeta
counter (Perkin Elmer).
Evaluation of Results
[0550] For each experiment, a data stream of cpm values collected
from the Wallac Microbeta counter was downloaded to a Microsoft
Excel statistical application program. Calculations of IC.sub.50
values were made using the transformed-both-sides logistic dose
response program that uses mean cpm values from wells representing
maximum binding (total)(assay buffer) and mean cpm values from
wells representing minimum binding (NSB, 10 .mu.M mazindol).
Estimation of the IC.sub.50 values was completed on a log scale and
the line was fit between the maximum and minimum binding values.
The K.sub.i value is a function of the concentration of the
compound required to inhibit 50% of the radioligand (IC.sub.50
value) divided by the free radioligand concentration [L] divided by
the K.sub.D value plus one (K.sub.i=IC.sub.50/(1+[L]/K.sub.D)). The
K.sub.i value for these studies was determined by dividing the
IC.sub.50 value by a factor of 2.4 to account for the concentration
of .sup.3[H]-WIN 35,428 used in the assay.
[0551] Results are shown in the following table:
TABLE-US-00002 TABLE A hDAT hNET Binding RLM Structure Function
IC50 stability CHEMISTRY IC50 (nM) (nM) t1/2 (min) ##STR00085## 3.8
1908.2 11 ##STR00086## 1.9 671.4 12 ##STR00087## 5.3 6204.5 10
##STR00088## 6.4 4967.7 9 ##STR00089## 9.1 5455.3 7 ##STR00090##
4.2 2625.5 7 ##STR00091## 394.0 >30 ##STR00092## 9.7 509.1 7
##STR00093## 2.9 2158.5 6 ##STR00094## 99.6 997.5 >30
##STR00095## 18.4 3185.2 >30 ##STR00096## 327.7 262.3 >30
##STR00097## 146.0 386.1 >30 ##STR00098## 294.0 1871.8 6
##STR00099## 64.0 2325.5 5 ##STR00100## 143.0 267.1 29 ##STR00101##
104.0 >1000 pending
[0552] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges specific
embodiments therein are intended to be included.
[0553] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in its entirety.
[0554] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *